Sulfur derivatives as chemokine receptor modulators

ABSTRACT

The present invention relates to novel sulfur derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of chemokine receptors.

RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.13/315,615, filed Dec. 9, 2011, which claims the benefit of U.S.Provisional Application Ser. No. 61/423,940, filed Dec. 16, 2010, bothof which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel sulfur derivatives, processes forpreparing them, pharmaceutical compositions containing them and theiruse as pharmaceuticals as modulators of chemokine receptors. Theinvention relates specifically to the use of these compounds and theirpharmaceutical compositions to treat disorders associated with chemokinereceptor (CCR) modulation.

BACKGROUND OF THE INVENTION

Chemokines are a group of 7- to 14-kd peptides that play an importantrole in orchestrating leukocyte recruitment and migration duringinflammation, and therefore represent an important target foranti-inflammatory therapies (Wells et al., 2006). They act by binding toseven-transmembrane, G protein-coupled receptors, the chemokinereceptors. The chemokine system is complex, with about ˜50 chemokinesand 20 chemokine receptors identified in humans, often acting withredundancy, making selection of specific antagonists difficult (Gerardand Rollins, 2001). Genetic knockout strategies have confirmed theimportance of chemokines as regulators of immune function, but thedeletion of specific chemokines has led to only specific and relativelymild defects in the inflammatory response further emphasizing thecomplex redundancy of the system. Selectivity is crucial for use ofchemokine receptor antagonists in systemic diseases where a singlechemokine-receptor system is implicated such as atheroscelorsis wherethe macrophage/monocyte system is the major player in order to allow asubtle and specific control over immune function (Weisberg et al., 2006;Feria and Diaz Gonzalez et al., 2006).

Many ocular conditions are characterized by inappropriate migration andinfiltration of cells such as leukocytes and endothelial cells into theeye with deleterious effects to ocular structures (Wallace et al.,2004). Chemokines have been identified in such diseases andmisregulation of the chemokine system is apparent in corneal graftrejection, diabetic retinopathy, age-related macular degeneration(ARMD), chronic inflammatory diseases such as uveitis, dry eye etc. Micelacking CCR2 or MCP-1 develop features of ARMD with age, includingdrusen deposits, choroidal neovascularization and photoreceptor atrophyindicating a crucial role for this chemokine and its receptor signaling(Amabati et al., 2003). Thus CCR2 receptor-specific inhibitor might havepotential therapeutic benefit in ocular diseases like ARMD. In contrast,various human and animal studies have identified several chemokines indifferent forms of uveitis, produced both by resident and infiltratingcells, that strongly suggests a prominent role for these molecules inits pathogenesis. Studies in rat and mice models of uveitis havedemonstrated up-regulation of monocyte chemoattractant protein-1(MCP-1), macrophage inflammatory protein-1 (MIP-1), RANTES, stromalderived factor-1 (SDF-1) which are powerful chemoattractants formonocytes and T-cells (Fang et al., 2004; Keino et al., 2003). Similarfindings have been reported in peripheral blood mononuclear cells inpatients with acute anterior uveitis (AAU), the most common form ofhuman uveitis (Klitgaard et al., 2004). MCP-1 knockout mice and CCR5knockout mice show reduced endotoxin-induced uveitis, which is theanimal model for AAU (Takeuchi et al., 2005; Tuallion et al., 2002). Ithas also been demonstrated that blocking the chemokine system upstreamwith the use of NF-κB blockers significantly attenuates experimental AAUin rats (Yang et al., 2005). Blockage of NF-κB results intranscriptional inhibition of multiple chemokines. Given the complexityof pathogenesis in uveitis it is unlikely that a selective inhibition ofa chemokine receptor in monotherapy will offer therapeutic benefit. Asimilar role of multiple chemokines have been shown to be correlatedwith clinical stage of disease in diabetic retinopathy and dry eye(Meleth et al., 2005; Yamagami et al., 2005). In these ocular diseasesthe use of broad spectrum chemokine receptor inhibitor which inhibitsthe function of a wide range of chemokines may be beneficial.

The first broad spectrum chemokine inhibitor (BSCI) to be reported wastermed Peptide 3, which was derived from the sequence of human chemokineMCP-1 and was shown to block the migration of monocytes in response toMCP-1, MIP-1, RANTES and SDF-1 (Reckless and Grainger. 1999). A cyclicretro inverse analogue of Peptide 3, constructed of D-amino acids in thereverse sequence, called NR58-3.14.3 was observed to be a more potentchemokine inhibitor (Beech et al., 2001). NR58-3.14.3 has been used totest for anti-inflammatory activities in animal models ofatherosclerosis, lung inflammation, irritable bowel syndrome etc (Beechet al., 2001; Grainger and Reckless. 2003; Tokuyama et al., 2005).However there are several disadvantages to using these BSCI as along-term therapeutic strategy. The known BSCIs which are peptides whichhave relatively low potency, poor pharmacokinetics, and are unstable invivo. In addition, systemic use of broad spectrum chemokine receptorinhibitors could potentially lead to deleterious side effects due totheir systemic anti-inflammatory activity. However in ocular diseases, alocal or topical application would prevent the broad spectrum inhibitorto be taken up systemically. Identification of a small moleculeinhibitor of several chemokine receptors could be very useful fortreatment of inflammatory ocular diseases. Given the evidence for therole of multiple chemokines in several ocular diseases and theseresults, we propose that the use of small and large molecule broadspectrum chemokine receptor inhibitors will have utility in the localtreatment of ocular inflammatory diseases including, but not limited to,uveitis, dry eye, diabetic retinopathy, allergic eye disease andproliferative retinopathies. Manipulation of multiple chemokinestherefore represents a novel therapeutic approach in treating oculardiseases.

WO2008008374 discloses CCR2 inhibitors and methods of use thereof.

WO03/099773 discloses CCR9 inhibitors and methods of use thereof.

U.S. Pat. No. 7,622,583 discloses heteroaryl sulfonamides as antagonistsof the CCR2 receptor.

US 2008/0293720 discloses pyridinyl sulfonamide modulators of chemokinereceptors.

U.S. Pat. No. 7,393,873 discloses arylsulfonamide derivatives.

SUMMARY OF THE INVENTION

We have now discovered a group of novel sulphur derivatives which arepotent and selective chemokine receptor modulators. As such, thecompounds described herein are useful in treating a wide variety ofdisorders associated with modulation of chemokine receptors. The term“modulator” as used herein, includes but is not limited to: receptoragonist, antagonist, inverse agonist, inverse antagonist, partialagonist, partial antagonist.

This invention describes compounds of Formula I, which have chemokinereceptor biological activity. The compounds in accordance with thepresent invention are thus of use in medicine, for example in thetreatment of humans with diseases and conditions that are alleviated byCCR modulation.

In one aspect, the invention provides a compound having Formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the individual geometrical isomers, enantiomers,diastereoisomers, tautomers, zwitterions and pharmaceutically acceptablesalts thereof:

wherein:

-   R¹ is H-   R² is substituted or unsubstituted C₁₋₆ alkyl, substituted or    unsubstituted C₃₋₈ cycloalkyl or is substituted or unsubstituted    C₃₋₈ cycloalkenyl;-   R⁵ is —S—, —S(O)—, or —S(O)₂—;-   R⁶ is substituted or unsubstituted heterocycle, substituted or    unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈    cycloalkenyl or is substituted or unsubstituted C₆₋₁₀ aryl;-   R¹⁷ is H, substituted or unsubstituted C₁₋₆ alkyl, halogen,    substituted or unsubstituted —OC₁₋₆ alkyl, CN, C(O)R¹⁹, NR²⁰R²¹ or    hydroxyl;-   R¹⁸ is H, substituted or unsubstituted C₁₋₆ alkyl, halogen,    substituted or unsubstituted —OC₁₋₆ alkyl, CN, C(O)R²², NR²³R²⁴ or    hydroxyl;-   R⁷ is H, halogen, CN, substituted or unsubstituted —OC₁₋₆ alkyl,    substituted or unsubstituted C₁₋₆ alkyl or is substituted or    unsubstituted C₃₋₈ cycloalkyl;-   R⁸ is H, substituted or unsubstituted C₁₋₆ alkyl, halogen,    substituted or unsubstituted —OC₁₋₆ alkyl, or hydroxyl;-   R¹⁹ is H, OH or substituted or unsubstituted C₁₋₆ alkyl-   R²⁰ is H or substituted or unsubstituted C₁₋₆ alkyl;-   R²¹ is H or substituted or unsubstituted C₁₋₆ alkyl;-   R²² is H, OH or substituted or unsubstituted C₁₋₆ alkyl-   R²³ is H or substituted or unsubstituted C₁₋₆ alkyl;-   R²⁴ is H or substituted or unsubstituted C₁₋₆ alkyl; and including    compounds:-   N-{2-[(3-aminobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;    and-   N-{2-[(3-aminobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;    and with the provisos that-   a). R⁷, R⁸, R¹⁷ and R¹⁸ cannot all be H in same time;-   b). when R⁸ is substituted or unsubstituted C₁₋₆ alkyl, the alkyl    group does not contain a carbonyl group directly attached to the    phenyl ring;-   c). the compound is not of the following structures:

In another aspect, the invention provides a compound having Formula Iwherein:

-   R¹ is H;-   R² is substituted or unsubstituted C₁₋₆ alkyl, substituted or    unsubstituted C₃₋₈ cycloalkyl or substituted or unsubstituted C₃₋₈    cycloalkenyl;-   R⁵ is S;-   R⁶ is substituted or unsubstituted heterocycle, substituted or    unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈    cycloalkenyl or substituted or unsubstituted C₆₋₁₀ aryl;-   R¹⁷ is H, substituted or unsubstituted C₁₋₆ alkyl, halogen,    substituted or unsubstituted —OC₁₋₆ alkyl, CN, C(O)R¹⁹, NR²⁰R²¹ or    hydroxyl;-   R¹⁸ is H, C₁₋₆ alkyl, halogen, substituted or unsubstituted —OC₁₋₆    alkyl, CN, C(O)R²², NR²³R²⁴ or hydroxyl;-   R⁷ is H, halogen, CN, substituted or unsubstituted —OC₁₋₆ alkyl,    substituted or unsubstituted C₁₋₆ alkyl or substituted or    unsubstituted C₃₋₈ cycloalkyl;-   R⁸ is H, substituted or unsubstituted C₁₋₆ alkyl, halogen,    substituted or unsubstituted —OC₁₋₆ alkyl, or hydroxyl;-   R¹⁹ is H, OH or substituted or unsubstituted C₁₋₆ alkyl;-   R²⁰ is H or substituted or unsubstituted C₁₋₆ alkyl;-   R²¹ is H or substituted or unsubstituted C₁₋₆ alkyl;-   R²² is H, OH or substituted or unsubstituted C₁₋₆ alkyl;-   R²³ is H or substituted or unsubstituted C₁₋₆ alkyl; and-   R²⁴ is H or substituted or unsubstituted C₁₋₆ alkyl; and with the    provisos that-   a). R⁷, R⁸, R¹⁷ and R¹⁸ cannot all be H in same time;-   b). when R⁸ is substituted or unsubstituted C₁₋₆ alkyl, the alkyl    group does not contain a carbonyl group directly attached to the    phenyl ring;-   c). the compound is not of the following structures:

In another aspect, the invention provides a compound having Formula Iwherein:

-   R¹ is H;-   R² is substituted or unsubstituted C₁₋₆ alkyl, substituted or    unsubstituted C₃₋₈ cycloalkyl or substituted or unsubstituted C₃₋₈    cycloalkenyl;-   R⁵ is —S(O)—;-   R⁶ is substituted or unsubstituted heterocycle, substituted or    unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈    cycloalkenyl or substituted or unsubstituted C₆₋₁₀ aryl;-   R¹⁷ is H, substituted or unsubstituted C₁₋₆ alkyl, halogen,    substituted or unsubstituted —OC₁₋₆ alkyl, CN, C(O)R¹⁹, NR²⁰R²¹ or    hydroxyl;-   R¹⁸ is H, substituted or unsubstituted C₁₋₆ alkyl, halogen,    substituted or unsubstituted —OC₁₋₆ alkyl, CN, C(O)R²², NR²³R²⁴ or    hydroxyl;-   R⁷ is H, halogen, CN, substituted or unsubstituted —OC₁₋₆ alkyl,    substituted or unsubstituted C₁₋₆ alkyl or substituted or    unsubstituted C₃₋₈ cycloalkyl;-   R⁸ is H, substituted or unsubstituted C₁₋₆ alkyl, halogen,    substituted or unsubstituted —OC-₁₋₆ alkyl, or hydroxyl;-   R¹⁹ is H, OH or substituted or unsubstituted C₁₋₆ alkyl;-   R²⁰ is H or substituted or unsubstituted C₁₋₆ alkyl;-   R²¹ is H or substituted or unsubstituted C₁₋₆ alkyl;-   R²² is H, OH or substituted or unsubstituted C₁₋₆ alkyl;-   R²³ is H or substituted or unsubstituted C₁₋₆ alkyl; and-   R²⁴ is H or substituted or unsubstituted C₁₋₆ alkyl; and with the    provisos that-   a). R⁷, R⁸, R¹⁷ and R¹⁸ cannot all be H in same time;-   b). when R⁸ is substituted or unsubstituted C₁₋₆ alkyl, the alkyl    group does not contain a carbonyl group directly attached to the    phenyl ring;-   c). the compound is not of the following structure:

In another aspect, the invention provides a compound having Formula Iwherein:

-   R¹ is H;-   R² is substituted or unsubstituted C₁₋₆ alkyl, substituted or    unsubstituted C₃₋₈ cycloalkyl or substituted or unsubstituted C₃₋₈    cycloalkenyl;-   R⁵ is —S(O)₂—;-   R⁶ is heterocycle, substituted or unsubstituted C₃₋₈ cycloalkyl,    substituted or unsubstituted C₃₋₈ cycloalkenyl or substituted or    unsubstituted C₆₋₁₀ aryl;-   R¹⁷ is H, substituted or unsubstituted C₁₋₆ alkyl, halogen, —OC₁₋₆    alkyl, CN, C(O)R¹⁹, NR²⁰R²¹ or hydroxyl;-   R¹⁸ is H, substituted or unsubstituted C₁₋₆ alkyl, halogen,    substituted or unsubstituted —OC₁₋₆ alkyl, CN, C(O)R²², NR²³R²⁴ or    hydroxyl;-   R⁷ is H, halogen, CN, substituted or unsubstituted —OC₁₋₆ alkyl,    substituted or unsubstituted C₁₋₆ alkyl or substituted or    unsubstituted C₃₋₈ cycloalkyl;-   R⁸ is H, substituted or unsubstituted C₁₋₆ alkyl, halogen, —OC₁₋₆    alkyl, or hydroxyl;-   R¹⁹ is H, OH or substituted or unsubstituted C₁₋₆ alkyl;-   R²⁰ is H or substituted or unsubstituted C₁₋₆ alkyl;-   R²¹ is H or substituted or unsubstituted C₁₋₆ alkyl;-   R²² is H, OH or substituted or unsubstituted C₁₋₆ alkyl;-   R²³ is H or substituted or unsubstituted C₁₋₆ alkyl; and-   R²⁴ is H or substituted or unsubstituted C₁₋₆ alkyl; and with the    provisos that-   a). R⁷, R⁸, R¹⁷ and R¹⁸ cannot all be H in same time;-   b). when R⁸ is substituted or unsubstituted C₁₋₆ alkyl, the alkyl    group does not contain a carbonyl group directly attached to the    phenyl ring;-   c). the compound is not of the following structures:

In another aspect, the invention provides a compound having Formula Iwherein:

-   R¹ is H;-   R² is substituted or unsubstituted C₁₋₆ alkyl, substituted or    unsubstituted C₃₋₈ cycloalkyl or substituted or unsubstituted C₃₋₈    cycloalkenyl;-   R⁵ is —S—, —S(O)—, or —S(O)₂—;-   R⁶ is substituted or unsubstituted heterocycle or substituted or    unsubstituted C₆₋₁₀ aryl;-   R¹⁷ is H, substituted or unsubstituted C₁₋₆ alkyl or halogen;-   R¹⁸ is H, substituted or unsubstituted C₁₋₆ alkyl or halogen;-   R⁷ is halogen, CN, —OC₁₋₆ alkyl, substituted or unsubstituted C₁₋₆    alkyl or substituted or unsubstituted C₃₋₈ cycloalkyl;-   R⁸ is H, substituted or unsubstituted C₁₋₆ alkyl or halogen; and    with the provisos that:-   b). when R⁸ is substituted or unsubstituted C₁₋₆ alkyl, the alkyl    group does not contain a carbonyl group directly attached to the    phenyl ring;-   c). the compound is not of the following structures:

In another aspect, the invention provides a compound having Formula Iwherein:

-   R¹ is H-   R² is substituted or unsubstituted C₁₋₆ alkyl, substituted or    unsubstituted C₃₋₈ cycloalkyl or substituted or unsubstituted C₃₋₈    cycloalkenyl;-   R⁵ is —S—;-   R⁶ is substituted or unsubstituted heterocycle or substituted or    unsubstituted C₆₋₁₀ aryl;-   R¹⁷ is H, substituted or unsubstituted C₁₋₆ alkyl or halogen;-   R¹⁸ is H, substituted or unsubstituted C₁₋₆ alkyl or halogen;-   R⁷ is halogen, CN, substituted or unsubstituted —OC₁₋₆ alkyl,    substituted or unsubstituted C₁₋₆ alkyl or substituted or    unsubstituted C₃₋₈ cycloalkyl;-   R⁸ is H, substituted or unsubstituted C₁₋₆ alkyl or halogen.; and    with the provisos that-   b). when R⁸ is substituted or unsubstituted C₁₋₆ alkyl, the alkyl    group does not contain a carbonyl group directly attached to the    phenyl ring;-   c). the compound is not of the following structures:

In another aspect, the invention provides a compound having Formula Iwherein:

-   R¹ is H;-   R² is substituted or unsubstituted C₁₋₆ alkyl, substituted or    unsubstituted C₃₋₈ cycloalkyl or substituted or unsubstituted C₃₋₈    cycloalkenyl;-   R⁵ is —S(O)—;-   R⁶ is substituted or unsubstituted heterocycle or substituted or    unsubstituted C₆₋₁₀ aryl;-   R¹⁷ is H, substituted or unsubstituted C₁₋₆ alkyl or halogen;-   R¹⁸ is H, substituted or unsubstituted C₁₋₆ alkyl or halogen;-   R⁷ is halogen, CN, —OC₁₋₆ alkyl, substituted or unsubstituted C₁₋₆    alkyl or substituted or unsubstituted C₃₋₈ cycloalkyl;-   R⁸ is H, substituted or unsubstituted C₁₋₆ alkyl or halogen; and    with the proviso that-   b). when R⁸ is substituted or unsubstituted C₁₋₆ alkyl, the alkyl    group does not contain a carbonyl group directly attached to the    phenyl ring.

In another aspect, the invention provides a compound having Formula Iwherein:

-   R¹ is H;-   R² is substituted or unsubstituted C₁₋₆ alkyl, substituted or    unsubstituted C₃₋₈ cycloalkyl or substituted or unsubstituted C₃₋₈    cycloalkenyl;-   R⁵ is —S(O)₂—;-   R⁶ is substituted or unsubstituted heterocycle or substituted or    unsubstituted C₆₋₁₀ aryl;-   R¹⁷ is H, substituted or unsubstituted C₁₋₆ alkyl or halogen;-   R¹⁸ is H, substituted or unsubstituted C₁₋₆ alkyl or halogen;-   R⁷ is halogen, CN, substituted or unsubstituted —OC₁₋₆ alkyl,    substituted or unsubstituted C₁₋₆ alkyl or substituted or    unsubstituted C₃₋₈ cycloalkyl;-   R⁸ is H, substituted or unsubstituted C₁₋₆ alkyl or halogen; and    with the proviso that-   b). when R⁸ is substituted or unsubstituted C₁₋₆ alkyl, the alkyl    group does not contain a carbonyl group directly attached to the    phenyl ring.

In another aspect, the invention provides a compound having Formula Iwherein:

-   R¹ is H;-   R² is substituted or unsubstituted C₁₋₆ alkyl;-   R⁵ is —S—, —S(O)—, or —S(O)₂—;-   R⁶ is substituted or unsubstituted heterocycle or substituted or    unsubstituted phenyl;-   R¹⁷ is H;-   R¹⁸ is H;-   R⁷ is halogen, CN, substituted or unsubstituted —OC₁₋₆ alkyl;-   R⁸ is H; and-   with the proviso that-   c). the compound is not of the following structures:

In another aspect, the invention provides a compound having Formula Iwherein:

-   R¹ is H;-   R² is C₁₋₆ alkyl;-   R⁵ is —S;-   R⁶ is substituted or unsubstituted heterocycle or substituted or    unsubstituted phenyl;-   R¹⁷ is H;-   R¹⁸ is H;-   R⁷ is halogen, CN or substituted or unsubstituted —OC₁₋₆ alkyl;-   R⁸ is H; and-   with the proviso that-   c). the compound is not of the following structures:

In another aspect, the invention provides a compound having Formula Iwherein:

-   R¹ is H;-   R² is substituted or unsubstituted C₁₋₆ alkyl;-   R⁵ is —S(O);-   R⁶ is substituted or unsubstituted heterocycle or substituted or    unsubstituted phenyl;-   R¹⁷ is H;-   R¹⁸ is H;-   R⁷ is halogen, CN or —OC₁₋₆ alkyl;-   R⁸ is H.

In another aspect, the invention provides a compound having Formula Iwherein:

-   R¹ is H;-   R² is substituted or unsubstituted C₁₋₆ alkyl;-   R⁵ is —S(O)₂—;-   R⁶ is substituted or unsubstituted heterocycle or substituted or    unsubstituted phenyl;-   R¹⁷ is H;-   R¹⁸ is H;-   R⁷ is halogen, CN or —OC₁₋₆ alkyl;-   R⁸ is H.

In another aspect, the invention provides a compound having Formula Iwherein:

-   R¹ is H;-   R² is methyl, isopropyl, 2-hydroxyethyl, methylpropionate,    2-methylpyridine, ethylacetate, N,N-dimethylpropanamide,    N-isopropylpropanamide, propamide, hydroxycyclopentyl, ethyl,    N,N-dimethylacetamide, N-methylacetamide, 2-aminoethyl,    H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl,    2-[(aminocarbonyl)amino]ethyl, tert-butyl pyridin-2-yl-carbamate,    6-aminopyridin-2-yl, 2-oxo-1,3-oxazolidin-5-yl-methyl,    2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl, 3-aminopropyl,    N,N-dimethylbutanamide, 1H-pyrazol-3-ylmethyl,    methyl-1,3-thiazol-2-yl-acetamide,    tert-butyl-1,3-thiazol-2-yl-carbamate,    2-amino-1,3-thiazol-4-yl)methyl, 3-methyl pyridine, 3-nitrobenzyl,    3-methoxybenzyl, 5-nitro-1H-pyrazol-3-yl-methyl,    5-amino-1H-pyrazol-3-yl-methyl, 1-propyl-1H-imidazol-4-yl)methyl,    tert-butyl-1-oxidopyridin-2-yl-carbamate, 3-hydroxybenzyl,    5-amino-4H-1,2,4-triazol-3-yl)methyl, 2-pyridin-2-ylethyl,    2-(1H-pyrazol-4-yl)ethyl, 2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl,    (2-fluoropyridin-3-yl)methyl, trifluoromethyl, benzyl,    3-nitrobenzyl, 4-nitrobenzyl, 2-aminobenzyl, 3-aminobenzyl or    pyrimidin-2-ylmethyl;-   R⁵ is —S(O)₂—, —S— or —S(O)—;-   R⁶ is 4-chloro-3-trifluoromethyl-phenyl, 3,4-dichlorophenyl,    3-methoxyphenyl, 4-methyl-3-nitrophenyl, 4-chlorophenyl,    4-chloro-3-methylphenyl, 4-nitro-3-trifluoromethylphenyl,    2,4-difluorophenyl, 4-chloro-2-fluorophenyl,    3-chloro-2-fluorophenyl, 4-isopropylphenyl, 4-bromophenyl,    4-iodophenyl, 3-chlorophenyl, 2-benzofuran, 5-methyl-2-furan,    2-furan or phenyl;-   R⁷ is chlorine, cyano, methoxy or fluorine;-   R¹⁷ is H;-   R¹⁸ is H; and-   R⁸ is H.

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 6 carbon atoms. One or moremethylene (—CH₂—) groups, of the alkyl can be replaced by oxygen,sulfur, carbonyl, sulfoxide, nitrogen, sulfonyl, or by a divalent C₃₋₆cycloalkyl. Hydrogen atoms on alkyl groups can be substituted by groupsincluding, but not limited to: halogen, —OH, C₃₋₈ cycloalkyl,non-aromatic heterocycles, aromatic heterocycles, C₆₋₁₀ aryl, —O(C₁₋₆alkyl), amine groups, amino groups, NO₂, amide groups, sulfonamidegroups, ester groups, aldehyde groups, carboxylic acids, ketone groups.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be substituted by groups including, but not limited to:halogen, —OH, C₃₋₈ cycloalkyl, non-aromatic heterocycles, aromaticheterocycles, C₆₋₁₀ aryl, —O(C₁₋₆ alkyl), amine groups, amino groups,NO₂, amide groups, carboxylic acids, sulfonamide groups, ester groups,aldehyde groups, ketone groups.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturatedcycloalkyl having one or more double bonds. Cycloalkenyl groups can bemonocyclic or polycyclic. Cycloalkenyl groups can be substituted bygroups including, but not limited to halogen, —OH, C₃₋₈ cycloalkyl,non-aromatic heterocycles, aromatic heterocycles, C₆₋₁₀ aryl, —O(C₁₋₆alkyl), amine groups, amino groups, NO₂, amide groups, sulfonamidegroups,carboxylic acids, ester groups, aldehyde groups, ketone groups.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. C₂₋₆ alkenyl can be in the E orZ configuration. Alkenyl groups can be substituted by C₁₋₃ alkyl.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or non-saturated,containing at least one heteroatom selected form O or N or S orcombinations of at least two thereof, interrupting the carbocyclic ringstructure. The heterocyclic ring can be interrupted by a C═O; the Sheteroatom can be oxidized. Heterocycles can be monocyclic orpolycyclic. Heterocyclic ring moieties can be substituted groupsincluding, but not limited to: halogens, —OH, C₃₋₈ cycloalkyl,non-aromatic heterocycles, aromatic heterocycles, —OC₁₋₆ alkyl, —NH₂,—NO₂, amides, ethers, esters, ketones, carboxylic acids, aldehydes,sulfonamides groups.

Preferred substituted heterocycle groups are, but not limited to:pyridine, furan, azetidine, thiazol, thiophene, oxazol, pyrazol,isoxazole, 2-oxoindoline, 2-oxo-2,3-dihydro-1,3-benzoxazole,2-oxo-2H-chromene, imidazole[2,1-b]thiazole, 1-H-pyrazole, indole,imidazole, quinoline, 2-thiophene, 2-benzofuran, 5-methyl-2-furan,5-oxazolidine-2-one, pyrimidine-2,4(1H,3H)-dione, pyrimidine.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen. Aryl can be substituted by groupsincluding, but not limited to: halogens, —OH, C₃₋₈ cycloalkyl,non-aromatic heterocycles, aromatic heterocycles, —OC₁₋₆ alkyl, —NH₂,—NO₂, amides, ethers, esters, carboxylic acids, aldehydes, ketones,sulfonamides groups. Aryl can be monocyclic or bicyclic. Preferredsubstituted phenyl groups are, but not limited to:4-chloro-3-trifluoromethyl-phenyl, 3,4-dichlorophenyl, 3-methoxyphenyl,4-methyl-3-nitrophenyl, 4-chlorophenyl, 4-chloro-3-methylphenyl,nitro-3-trifluoromethylphenyl, 2,4-difluorophenyl,4-chloro-2-fluorophenyl, 3-chloro-2-fluorophenyl, 4-isopropylphenyl,4-bromophenyl, 4-iodophenyl, 3-chlorophenyl.

The term “amine” as used herein, represents a group of formula“—NR^(x)R^(y) “wherein R^(x) and R^(y) can be the same or independentlyH, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “amide” as used herein, represents a group of formula“—C(O)NR^(x)R^(y),” or “—C(O)N(R^(x))(R^(y))” or “NR^(x)C(O)R^(y)”wherein R^(x) and R^(y) can be the same or independently H, alkyl, aryl,cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “sulfonamide” as used herein, represents a group of formula“—S(O)₂NR^(x)R^(y)” or “NR^(x)R^(y)S(O)₂” or “—NR^(x)S(O)₂R^(y)” whereinR^(x) and R^(y) can be the same or independently H, alkyl, aryl,cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “ester” as used herein, represents a group of formula“—C(O)O(R^(x))”, wherein R^(x) is alkyl, aryl, cycloalkyl, cycloalkenyl,heterocycle as defined above.

The term “aldehyde” as used herein, represents a group of formula“—C(O)H”.

The term “ketone” as used herein, represents a group of formula “—C(O)R^(x)” wherein R^(x) is C₁₋₆ alkyl.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “amino” as used herein, represents a group of formula “—NH₂”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)”.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula“—SO₂”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—38 .

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “sulfoxide” as used herein, represents a group of formula“—S═O”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—(O)P(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

Some compounds of the invention are:

-   4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-[5-chloro-2-(methylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-[5-chloro-2-(isopropylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-[5-chloro-2-(isopropylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   methyl    3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propanoate;-   4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(pyridin-2-y    methyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   ethyl{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}acetate;-   3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-isopropylpropanamide;-   3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylpropanamide;-   3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-isopropylpropanamide;-   3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylpropanamide;-   3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propanamide;-   N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide;-   3,4-dichloro-N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide;-   N-[5-chloro-2-(methylthio)phenyl]thiophene-2-sulfonamide;-   N-[5-chloro-2-(methylsulfinyl)phenyl]thiophene-2-sulfonamide;-   4-chloro-N-{5-chloro-2-[(3-hydroxycyclopentyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(3-hydroxycyclopentyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-[5-chloro-2-(ethylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-[5-chloro-2-(ethylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-[5-chloro-2-(ethylsulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;-   N-[5-chloro-2-(methylthio)phenyl]-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(methylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(methylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-[5-chloro-2-(methylthio)phenyl]-4-methyl-3-nitrobenzenesulfonamide;-   4-chloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide;-   4-chloro-N-[5-chloro-2-(methylthio)phenyl]-3-methylbenzenesulfonamide;-   N-[5-chloro-2-(methylsulfinyl)phenyl]-4-methyl-3-nitrobenzenesulfonamide;-   N-[5-chloro-2-(methylsulfonyl)phenyl]-4-methyl-3-nitrobenzenesulfonamide;-   4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide;-   4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]benzenesulfonamide;-   4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3-methylbenzenesulfonamide;-   4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-3-methylbenzenesulfonamide;-   2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylacetamide;-   2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-methylacetamide;-   2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylacetamide;-   2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylacetamide;-   2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-methylacetamide;-   2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N-methylacetamide;-   N-{2-[(2-aminoethyl)thio]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide;-   N-[5-chloro-2-(methylthio)phenyl]-3-nitro-4-(trifluoromethyl)benzenesulfonamide;-   N-[5-chloro-2-(methylsulfonyl)phenyl]-3-nitro-4-(trifluoromethyl)benzenesulfonamide;-   N-[5-chloro-2-(methylthio)phenyl]-2,4-difluorobenzenesulfonamide;-   N-[5-chloro-2-(methylsulfonyl)phenyl]-2,4-difluorobenzenesulfonamide;-   N-[5-chloro-2-(methylsulfinyl)phenyl]-2,4-difluorobenzenesulfonamide;-   N-[5-chloro-2-(methylsulfinyl)phenyl]-3-nitro-4-(trifluoromethyl)benzenesulfonamide;-   N-[5-chloro-2-(methylthio)phenyl]-5-methylfuran-2-sulfonamide;-   N-[5-chloro-2-(methylsulfinyl)phenyl]-5-methylfuran-2-sulfonamide;-   N-[5-chloro-2-(methylsulfonyl)phenyl]-5-methylfuran-2-sulfonamide;-   N-[5-chloro-2-(methylthio)phenyl]furan-2-sulfonamide;-   N-[5-chloro-2-(methylsulfinyl)phenyl]furan-2-sulfonamide;-   N-[5-chloro-2-(methylsulfonyl)phenyl]furan-2-sulfonamide;-   N-{2-[(2-aminoethyl)sulfonyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide;-   3-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide;-   3-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-2-fluorobenzenesulfonamide;-   3-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-2-fluorobenzenesulfonamide;-   4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-2-fluorobenzenesulfonamide;-   4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-2-fluorobenzenesulfonamide;-   N-{2-[(2-aminoethyl)sulfinyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;-   N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)-N,N-dimethylpropanamide;-   3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)-N,N-dimethylpropanamide;-   3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)-N,N-dimethylpropanamide;-   N-[2-({2-[(aminocarbonyl)amino]ethyl}thio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide;-   N-[2-({2-[(aminocarbonyl)amino]ethyl}sulfinyl)-5-chlorophenyl]-1-benzofuran-2-sulfonamide;-   N-[2-({2-[(aminocarbonyl)amino]ethyl}sulfonyl)-5-chlorophenyl]-1-benzofuran-2-sulfonamide;-   tert-butyl{6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]pyridin-2-yl}carbamate;-   N-(2-{[(6-aminopyridin-2-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   N-(2-{[(6-aminopyridin-2-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   N-(2-{[(6-aminopyridin-2-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   N-(2-{[(6-amino-1-oxidopyridin-2-yl)methyl]sulfonyl}-5-chlorophenyol)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[3-(dimethylamino)propyl]thio}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[3-(dimethylamino)propyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[3-(dimethylamino)propyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[3-(dimethylnitroryl)propyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}ethyl)acetamide;-   N-(2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}ethyl)acetamide;-   N-(5-chloro-2-{[(2-oxo-1,3-oxazolidin-5-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(2-oxo-1,3-oxazolidin-5-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminopropyl)thio]-5-chlorophenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminopropyl)sulfinyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminopropyl)sulfonyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide;-   4-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)-N,N-dimethylbutanamide;-   4-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)-N,N-dimethylbutanamide;-   5-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide;-   5-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(1H-pyrazol-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(1H-pyrazol-3-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(1H-pyrazol-3-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}acetamide;-   N-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]-1,3-thiazol-2-yl}acetamide;-   N-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]-1,3-thiazol-2-yl}acetamide;-   N-[5-chloro-2-(methylsulfinyl)phenyl]-4-isopropylbenzenesulfonamide;-   4-bromo-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide;-   N-[5-chloro-2-(methylthio)phenyl]-4-iodobenzenesulfonamide;-   N-[5-chloro-2-(methylsulfonyl)phenyl]-4-isopropylbenzenesulfonamide;-   4-bromo-N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide;-   N-[5-chloro-2-(methylsulfinyl)phenyl]-4-iodobenzenesulfonamide;-   4-bromo-N-[5-chloro-2-(methylsulfonyl)phenyl]benzenesulfonamide;-   N-[5-chloro-2-(methylsulfonyl)phenyl]-4-iodobenzenesulfonamide;-   tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}carbamate;-   N-(2-{[(2-amino-1,3-thiazol-4-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]-1,3-thiazol-2-yl}carbamate;-   N-(2-{[(2-amino-1,3-thiazol-4-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]-1,3-thiazol-2-yl}carbamate;-   N-(2-{[(2-amino-1,3-thiazol-4-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(1-oxidopyridin-3-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(1-oxidopyridin-3-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(3-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(3-methoxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(2-{[(5-amino-1H-pyrazol-3-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   N-(2-{[(5-amino-1H-pyrazol-3-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   N-(2-{[(5-amino-1H-pyrazol-3-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(1-oxidopyridin-2-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(1-oxidopyridin-2-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide;-   tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate;-   N-(2-{[(2-aminopyridin-4-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]pyridin-2-yl}carbamate;-   tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]-1-oxidopyridin-2-yl}carbamate;-   N-(2-{[(2-aminopyridin-4-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   N-(2-{[(2-aminopyridin-4-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   N-(2-{[(2-amino-1-oxidopyridin-4-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-1-benzofuran-2-sulfonamide-   N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(3-hydroxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(3-hydroxybenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(3-hydroxybenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylpropanamide;-   3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide;-   N-(2-{[(5-amino-4H-1,2,4-triazol-3-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   N-(2-{[(5-amino-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide;-   3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)sulfinyl]-N,N-dimethylpropanamide;-   3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)sulfonyl]-N,N-dimethylpropanamide;-   3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide;-   3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]-N,N-dimethylpropanamide;-   3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]-N,N-dimethylpropanamide;-   N-{5-chloro-2-[(2-pyridin-2-ylethyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[2-(1H-pyrazol-4-yl)ethyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(2-pyridin-2-ylethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(2-pyridin-2-ylethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[2-(1    H-pyrazol-4-yl)ethyl]thio}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[2-(1H-pyrazol-4-yl)ethyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]thio}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(trifluoromethyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(trifluoromethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(trifluoromethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-[2-(benzylthio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfinyl)-5-chlorophenyl]-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfonyl)-5-chlorophenyl]-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)thio]-5-fluorophenyl}-1-benzofuran-2-sulfonamide;-   N-{5-fluoro-2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfinyl]-5-fluorophenyl}-1-benzofuran-2-sulfonamide;-   N-{5-fluoro-2-[(3-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfonyl]-5-fluorophenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)thio]-5-methoxyphenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfonyl]-5-methoxyphenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-methoxy-2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfinyl]-5-methoxyphenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(4-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(2-aminobenzyl)thio]-5-chlorophenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(4-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(4-aminobenzyl)sulfonyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(2-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(2-aminobenzyl)sulfinyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(2-aminobenzyl)sulfonyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-2,4-difluorobenzenesulfonamide;-   N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-4-chloro-2-fluorobenzenesulfonamide;-   N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-2,4-difluorobenzenesulfonamide;-   N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-2,4-difluorobenzenesulfonamide;-   N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-4-chloro-2-fluorobenzenesulfonamide;-   N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-4-chloro-2-fluorobenzenesulfonamide;-   N-{5-chloro-2-[(pyrimidin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(pyrimidin-2-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{5-chloro-2-[(pyrimidin-2-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide;-   N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}benzenesulfonamide;-   N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-4-chlorobenzenesulfonamide;-   N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-3-chlorobenzenesulfonamide;-   N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}benzenesulfonamide;-   N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}benzenesulfonamide;-   N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-4-chlorobenzenesulfonamide;-   N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-4-chlorobenzenesulfonamide;-   N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-3-chlorobenzenesulfonamide;-   N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-3-chlorobenzenesulfonamide;-   N-[2-(benzylthio)-5-cyanophenyl]-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfinyl)-5-cyanophenyl]-1-benzofuran-2-sulfonamide;-   N-[2-(benzylsulfonyl)-5-cyanophenyl]-1-benzofuran-2-sulfonamide.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicacid, such as hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, nitric acid and the like; or an organic acid such asfor example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid,malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid,citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic and thelike (Handbook of Pharmaceutical Salts, P. Heinrich Stahal & Camille G.Wermuth (Eds), Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

The base addition salt form of a compound of Formula I that occurs inits acid form can be obtained by treating the acid with an appropriatebase such as an inorganic base, for example, sodium hydroxide, magnesiumhydroxide, potassium hydroxide, Calcium hydroxide, ammonia and the like;or an organic base such as for example, L-Arginine, ethanolamine,betaine, benzathine, morpholine and the like. (Handbook ofPharmaceutical Salts, P. Heinrich Stahal& Camille G. Wermuth (Eds),Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the chemokine receptors.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of chemokine receptors.Such methods can be performed, for example, by administering to asubject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated byCCR modulation.

Therapeutic utilities of CCR modulators are skin inflammatory diseasesand conditions, including, but are not limited to: rosacea (dilation ofthe blood vessels just under the skin), sunburn, chronic sun damage,discreet erythemas, psoriasis, atopic dermatitis, menopause-associatedhot flashes, hot flashes resulting from orchiectomyatopic dermatitis,photoaging, seborrheic dermatitis, acne, allergic dermatitis, irritantdermatitis, telangiectasia (dilations of previously existing small bloodvessels) of the face, rhinophyma (hypertrophy of the nose withfollicular dilation), red bubou nose, acne-like skin eruptions (may oozeor crust), burning or stinging sensation of the face, irritated andbloodshot and watery eyes, cutaneous hyperactivity with dilation ofblood vessels of the skin, Lyell's syndrome, Stevens-Johnson syndrome,erythema multiforme minor, erythema multiforme major and otherinflammatory skin diseases, actinic keratoses, arsenic keratoses,inflammatory and non-inflammatory acne, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,wound healing.

Therapeutic utilities of CCR modulators are ocular inflammatory diseasesincluding, but not limited to, uveitis, retinal degenerative conditions,angiogenesis, dry eye, Keratitis, allergic eye disease and conditionsaffecting the posterior part of the eye, such as maculopathies andretinal degeneration including non-exudative age related maculardegeneration, exudative age related macular degeneration, choroidalneovascularization, diabetic retinopathy, acute macularneuroretinopathy, central serous chorioretinopathy, cystoid macularedema, and diabetic macular edema; uveitis, retinitis, and choroiditissuch as acute multifocal placoid pigment epitheliopathy, Behcet'sdisease, birdshot retinochoroidopathy, infectious (syphilis, lyme,tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis),multifocal choroiditis, multiple evanescent white dot syndrome (mewds),ocular sarcoidosis, posterior scleritis, serpiginous choroiditis,subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-and Haradasyndrome; vasuclar diseases/exudative diseases such as retinal arterialocclusive disease, central retinal vein occlusion, disseminatedintravascular coagulopathy, branch retinal vein occlusion, hypertensivefundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angiitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, and Ealesdisease; traumatic/surgical conditions such as sympathetic ophthalmia,uveitic retinal disease, retinal detachment, trauma, conditions causedby laser, conditions caused by photodynamic therapy, photocoagulation,hypoperfusion during surgery, radiation retinopathy, and bone marrowtransplant retinopathy; proliferative disorders such as proliferativevitreal retinopathy and epiretinal membranes, and proliferative diabeticretinopathy; infectious disorders such as ocular histoplasmosis, oculartoxocariasis, presumed ocular histoplasmosis syndrome (PONS),endophthalmitis, toxoplasmosis, retinal diseases associated with HIVinfection, choroidal disease associate with HIV infection, uveiticdisease associate with HIV infection, viral retinitis, acute retinalnecrosis, progressive outer retinal necrosis, fungal retinal diseases,ocular syphilis, ocular tuberculosis, diffuse unilateral subacuteneuroretinitis, and myiasis; genetic disorders such as retinitispigmentosa, systemic disorders with accosiated retinal dystrophies,congenital stationary night blindness, cone dystrophies, Stargardt'sdisease and fundus flavimaculatus, Best's disease, pattern dystrophy ofthe retinal pigmented epithelium, X-linked retinoschisis, Sorsby'sfundus dystrophy, benign concentric maculopathy, Bietti's crystallinedystrophy, and pseudoxanthoma elasticum; retinal tears/holes such asretinal detachment, macular hole, and giant retinal tear; tumors such asretinal disease associated with tumors, congenital hypertrophy of theretinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigement epitheliitis.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation of chemokinereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a therapeutically effective amount of atleast one compound of the invention, or any combination thereof, orpharmaceutically acceptable salts, hydrates, solvates, crystal forms andindividual isomers, enantiomers, and diastereomers thereof.

The present invention concerns the use of a compound of Formula I or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of ocular inflammatory diseases including,but not limited to, uveitis, dry eye, Keratitis, allergic eye diseaseand conditions affecting the posterior part of the eye, such asmaculopathies and retinal degeneration including non-exudative agerelated macular degeneration, exudative age related maculardegeneration, choroidal neovascularization, diabetic retinopathy, acutemacular neuroretinopathy, central serous chorioretinopathy, cystoidmacular edema, and diabetic macular edema; uveitis, retinitis, andchoroiditis such as acute multifocal placoid pigment epitheliopathy,Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis,lyme, tuberculosis, toxoplasmosis), intermediate uveitis (parsplanitis), multifocal choroiditis, multiple evanescent white dotsyndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginouschoroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-andHarada syndrome; vasuclar diseases/exudative diseases such as retinalarterial occlusive disease, central retinal vein occlusion, disseminatedintravascular coagulopathy, branch retinal vein occlusion, hypertensivefundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angiitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, and Ealesdisease; traumatic/surgical conditions such as sympathetic ophthalmia,uveitic retinal disease, retinal detachment, trauma, conditions causedby laser, conditions caused by photodynamic therapy, photocoagulation,hypoperfusion during surgery, radiation retinopathy, and bone marrowtransplant retinopathy; proliferative disorders such as proliferativevitreal retinopathy and epiretinal membranes, and proliferative diabeticretinopathy; infectious disorders such as ocular histoplasmosis, oculartoxocariasis, presumed ocular histoplasmosis syndrome (PONS),endophthalmitis, toxoplasmosis, retinal diseases associated with HIVinfection, choroidal disease associate with HIV infection, uveiticdisease associate with HIV infection, viral retinitis, acute retinalnecrosis, progressive outer retinal necrosis, fungal retinal diseases,ocular syphilis, ocular tuberculosis, diffuse unilateral subacuteneuroretinitis, and myiasis; genetic disorders such as retinitispigmentosa, systemic disorders with accosiated retinal dystrophies,congenital stationary night blindness, cone dystrophies, Stargardt'sdisease and fundus flavimaculatus, Best's disease, pattern dystrophy ofthe retinal pigmented epithelium, X-linked retinoschisis, Sorsby'sfundus dystrophy, benign concentric maculopathy, Bietti's crystallinedystrophy, and pseudoxanthoma elasticum; retinal tears/ holes such asretinal detachment, macular hole, and giant retinal tear; tumors such asretinal disease associated with tumors, congenital hypertrophy of theretinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigement epitheliitis.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds and their pharmaceutically-acceptable salts may beadministered through different routes, including but not limited totopical eye drops, direct injection, application at the back of the eyeor formulations that may further enhance the long duration of actionssuch as a slow releasing pellet, suspension, gel, or sustained deliverydevices such as any suitable drug delivery system (DDS) known in theart. While topical administration is preferred, this compound may alsobe used in an intraocular implant as described in U.S. U.S. Pat. No.7,931,909.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists of chemokine receptors.Thus, in further embodiments of the invention, there are providedmethods for treating a disorder associated with modulation of chemokinereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one invention compound. Asused herein, the term “therapeutically effective amount” means theamount of the pharmaceutical composition that will elicit the biologicalor medical response of a subject in need thereof that is being sought bythe researcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. The synthetic schemes set forth below, illustrate howcompounds according to the invention can be made. Those skilled in theart will be able to routinely modify and/or adapt Scheme 1 to synthesizeany compounds of the invention covered by Formula I.

The described sulfur derivatives were prepared by general routes asshown in Scheme 1. In one route, an appropriately substituted2-amino-benzenethiol such as Intermediate A can react with anelectrophile such as a halide, tosylate, mesylate, enone, 2-enoate etc.in the presence of an acid or base to prepare sulfide Intermediate B.Alternatively, sulfide Intermediate B can be prepared by treatment ofIntermediate A with an alcohol under Mitsunobu conditions. Reaction ofIntermediate B with a sulfonyl chloride provides the sulfonamide ofFormula I wherein R⁵ is S. Further, upon treatment with an oxidant suchas meta-chloroperoxybenzoic acid, the compound of Formula I wherein R5is S affords the compound wherein R⁵ is S(O) or R⁵ is S(O)₂.

In another route, di-sulfide Intermediate E type can be obtained throughoxidation of an Intermediate A type. Reaction of Intermediate E with a,sulfonyl chloride provides sulfonamide Intermediate F. In situ orstepwise reduction of Intermediate F using polymer boundtriphenylphosphine or sodium borohydride, respectively, followed byreaction of the resulting benzenethiol with an electrophile affords thesulfonamide of Formula I wherein R⁵ is S.

Scheme 1 DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of protium ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACD version 8 and some intermediates'and reagents' names used in the examples were generated with softwaresuch as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISISDraw 2.5 SP1. In general, characterization of the compounds is performedaccording to the following methods:

NMR spectra are recorded on Varian 600 or Varian 300, in the indicatedsolvent at ambient temperature; chemical shifts in [ppm], couplingconstants in [Hz].

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates, were preparedaccording to published procedures. Solvents were purchased fromcommercial sources in appropriate quality and used as received. Airand/or moisture-sensitive reactions were run under an Ar— or N₂—atmosphere.

Usually the compounds of the invention were purified by chromatography:CombiFlash Companion and RediSep Rf silica gel 60 (0.04-0.063 mm);Preparative thin layer chromatography (PTLC): Analtech (silica gel 60F₂₅₄, 500 or 1000 μm).

The following abbreviations are used in the examples:

-   NH₃ ammonia-   CH₃CN acetonitrile-   CH₂Cl₂ dichloromethane-   DMF N,N-dimethylformamide-   NaOH sodium hydroxide-   MeOH methanol-   CD₃OD deuterated methanol-   HCl hydrochloric acid-   Na₂SO₄ sodium sulfate-   HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate)-   DIPEA N,N-Diisopropylethylamine-   CuI copper iodide-   Cs₂CO₃ cesium carbonate-   DMEDA N,N′-dimethylethylenediamine-   MgSO₄ magnesium sulfate-   EtOAc ethyl acetate-   CDCl₃ deuterated chloroform-   DMSO-d₆ deuterated dimethyl sulfoxide-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   K₂CO₃ potassium carbonate-   mCPBA meta-Chloroperoxybenzoic acid-   NaBH₄ sodium borohydride-   CaCl₂ calcium chloride

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

SPECIFIC EXAMPLE General Procedure A Intermediate 15-chloro-2-[(1H-imidazol-4-ylmethyl)thio]aniline

A mixture of 2-amino-4-chlorobenzenethiol (CAS 1004-00-8) (1.1 g, 7.1mmol), 4-(chloromethyl)-1H-imidazole hydrochloride (721 mg, 4.71 mmol)and K₂CO₃ (3.2 g, 23.6 mmol) in DMF (10 ml) was stirred at roomtemperature over night. The reaction mixture was poured into water (50ml) and extracted with ethyl acetate (2×50 ml). The organic layer waswashed with brine, dried over Na₂SO₄, concentrated in vacuo. The crudeproduct was purified by column chromatography on silica gel (0→100%ethyl acetate in hexane) to give Intermediate 1 as a solid (1.0 g, 60%).

¹H NMR (300 MHz, CD₃OD) δ 7.58 (s, 1H), 7.06 (d, J=8.20 Hz, 1H), 6.73(d, J=2.34 Hz, 1H), 6.65 (s, 1H), 6.48 (dd, J=2.34, 8.20 Hz, 1H), 3.86(s, 2H).

General Procedure B Compound 1N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

A mixture of Intermediate 1 (300 mg, 1.26 mmol) and1-benzofuran-2-sulfonyl chloride (273 mg, 1.26 mmol) in pyridine (4 ml)was heated at 100° C. overnight. Pyridine was removed under reducedpressure and the residue was purified by column chromatography on silicagel (10% MeOH in CH₂Cl₂) to give Compound 1 (157 mg, 30%).

¹H NMR (600 MHz, acetone-d₆) δ 7.94 (s, 1H), 7.73 (d, J=7.92 Hz, 1H),7.64 (d, J=2.35 Hz, 1H), 7.56 (d, J=8.51 Hz, 1H), 7.52 (d, J=8.22 Hz,1H), 7.44-7.49 (m, 1H), 7.42 (s, 1H), 7.28-7.37 (m, 1H), 7.11 (dd,J=2.35, 8.22 Hz, 1H), 6.97 (s, 1H), 3.91 (s, 2H).

Compound 2 N-[5-chloro-2-(methylthio)phenyl]-1-benzofuran-2-sulfonamide

Following General Procedure B, the title compound (243 mg, 60%) wasprepared from 5-chloro-2-(methylthio)aniline (CAS 16423-54-4) (200 mg,1.15 mmol) and 1-benzofuran-2-sulfonyl chloride (249 mg, 1.152 mmol).

¹H NMR (600 MHz, acetone-d₆) δ 7.75 (d, J=7.92 Hz, 1H), 7.60 (d, J=8.51Hz, 1H), 7.48-7.54 (m, 2H), 7.47 (d, J=2.35 Hz, 1H), 7.29-7.38 (m, 2H),7.22 (dd, J=2.35, 8.51 Hz, 1H), 2.22 (s, 3H).

General Procedure C Compound 3N-[5-chloro-2-(methylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide

To a solution of Compound 2 (194 mg, 0.554 mmol) in CH₂Cl₂ (6 ml) at 0°C. was added mCPBA (111 mg, ˜0.554 mmol). After it was stirred for 30min at 0° C., the mixture was separated into two portions. One portion(2 ml) was concentrated in vacuo and purified by column chromatographyon silica gel (0→100% ethyl acetate in hexane followed by 0→10% MeOH inCH₂Cl₂) to give the title compound as a solid (35 mg, 52%).

Alternatively, the title compound can be prepared by treating Compound 2with 1 equivalent of NaIO₄ in MeOH/CH₃CN and H₂O at 0° C. to roomtemperature.

In another alternative procedure, the title compound can be prepared bytreating Compound 2 with 1-1.4 equivalent of Oxone® in MeOH/CH₃CN andH₂O at room temperature.

¹H NMR (600 MHz, CDCl₃) δ 7.74 (d, J=1.76 Hz, 1H), 7.71 (d, J=8.22 Hz,1H), 7.52-7.59 (m, 2H), 7.49 (td, J=1.17, 7.78 Hz, 1H), 7.32-7.39 (m,1H), 7.25 (d, J=8.22 Hz, 1H), 7.15 (dd, J=1.91, 8.36 Hz, 1H), 2.88 (s,3H).

General Procedure D Compound 4N-[5-chloro-2-(methylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide

To the other portion (4 ml) of solution from Compound 3 was added mCPBA(111 mg, 0.554 mmol) and the reaction was stirred at room temperaturefor 1 h. The mixture was concentrated in vacuo and the residue waspurified by column chromatography on silica gel (0→100% ethyl acetate inhexane) to give the title compound as a solid (75 mg, 53%).

Alternatively, the title compound can be prepared by treating Compound 2with 2-3 equivalents of mCPBA at room temperature.

In another alternative procedure, the title compound can be prepared bytreating Compound 2 with 3 equivalents of Oxone® in MeOH/CH₃CN and H₂Oat room temperature.

¹H NMR (600 MHz, CDCl₃) δ 9.43 (s, 1H), 7.88 (d, J=1.76 Hz, 1H), 7.81(d, J=8.51 Hz, 1H), 7.72 (d, J=7.92 Hz, 1H), 7.61 (s, 1H), 7.47-7.57 (m,2H), 7.34-7.40 (m, 1H), 7.26 (s, 1H), 7.23 (dd, J=2.05, 8.51 Hz, 1H),3.05 (s, 3H).

Intermediate 2 5-chloro-2-(methylsulfinyl)aniline

Following General Procedure C, the title compound (914 mg, 84%) wasprepared from 5-chloro-2-(methylthio)aniline (1 g, 5.758 mmol).

¹H NMR (300 MHz, CD₃OD) δ 7.32 (d, J=8.20 Hz, 1H), 6.81 (d, J=2.05 Hz,1H), 6.72 (dd, J=1.76, 8.20 Hz, 1H), 2.86 (s, 3H).

Compound 53,4-dichloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide

Following General Procedure B, the title compound (52 mg, 21%) wasprepared from 5-chloro-2-(methylsulfinyl)aniline (Intermediate 2) (120mg, 0.635 mmol) and 3,4-dichlorobenzene-1-sulfonyl chloride (156 mg,0.635 mmol).

¹H NMR (300 MHz, CD₃OD) δ 7.87 (d, J=1.76 Hz, 1H), 7.55-7.70 (m, 2H),7.38 (s, 1H), 7.17-7.27 (m, 2H), 2.22 (s, 3H).

Compound 63,4-dichloro-N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide

Following General Procedure C, the title compound (28 mg, 52%) wasprepared from3,4-dichloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide (52 mg,0.136 mmol).

¹H NMR (300 MHz, acetone-d₆) δ 10.70 (br. s., 1H), 8.06 (s, 1H), 7.86(s, 2H), 7.44-7.59 (m, 2H), 7.34 (dd, J=1.90, 8.35 Hz, 1H), 2.84 (s,3H).

Compound 74-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3-methylbenzenesulfonamide

Following General Procedure B and C, the title compound (90 mg) wasprepared from 5-chloro-2-(methylthio)aniline and4-chloro-3-methylbenzene-1-sulfonyl chloride.

¹H NMR (600 MHz, CDCl₃) δ 10.62 (s, 1H), 7.82 (d, J=2.05 Hz, 1H), 7.71(dd, J=1.91, 8.36 Hz, 1H), 7.63 (d, J=2.05 Hz, 1H), 7.48 (d, J=8.51 Hz,1H), 7.02-7.15 (m, 2H), 2.81 (s, 3H), 2.43 (s, 3H).

Compound 8N-[5-chloro-2-(methylsulfinyl)phenyl]-3-nitro-4-(trifluoromethyl)benzenesulfonamide

Following General Procedure B and C, the title compound (43 mg) wasprepared from 5-chloro-2-(methylthio)aniline and4-nitro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.

¹H NMR (600 MHz, acetone-d₆) δ 8.25-8.35 (m, 2H), 8.11 (d, J=8.22 Hz,1H), 7.39-7.48 (m, 2H), 6.75 (dd, J=2.05, 8.22 Hz, 1H), 2.70 (s, 3H).

Compound 94-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide

Following General Procedure B, the title compound (380 mg, 66%) wasprepared from 5-chloro-2-(methylthio)aniline (273mg, 1.57 mmol) and4-chloro-2-fluorobenzene-1-sulfonyl chloride (360 mg, 1.57 mmol).

¹H NMR (300 MHz, acetone-d₆) δ 8.77 (br. s., 1H), 7.84 (t, J=8.06 Hz,1H), 7.53 (dd, J=1.90, 9.82 Hz, 1H), 7.35-7.48 (m, 3H), 7.25 (dd,J=2.20, 8.35 Hz, 1H), 2.34 (s, 3H).

Compound 104-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure B and D, the title compound (95 mg, 36%) wasprepared from 5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]aniline (301 mg,1.26 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride(351 mg, 1.26 mmol).

¹H NMR (600 MHz, acetone-d₆) δ 8.27 (s, 1H), 8.15 (d, J=8.22 Hz, 1H),7.81 (br. s., 1H), 7.73 (d, J=8.51 Hz, 1H), 7.68 (d, J=8.51 Hz, 1H),7.30 (s, 1H), 6.91 (dd, J=1.47, 8.51 Hz, 1H), 4.56 (br. s., 2H).

Intermediate 3 tert-butyl[4-(chloromethyl)-1,3-thiazol-2-yl]carbamate

A solution of 4-(chloromethyl)-1,3-thiazol-2-amine hydrochloride (530mg, 2.86 mmol), di-tert-butyl dicarbonate (750 mg, 3.44 mmol),triethylamine (0.6 ml, 4.30 mmol) and DMAP (cat. amount) in THF (10 ml)was stirred at room temperature overnight. The mixture was diluted withethyl acetate. washed with water and brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by column chromatography(30% ethyl acetate in hexane) to give the title compound as a solid (391mg, 45%).

¹H NMR (600 MHz, CD₃OD) δ 7.02 (s, 1H), 4.56 (s, 2H), 1.54 (s, 9H).

Intermediate 4tert-butyl(4-{[(2-amino-4-chlorophenyl)thio]methyl}-1,3-thiazol-2-yl)carbamate

Following General Procedure A, the title compound (588 mg, 67%) wasprepared from 2-amino-4-chlorobenzenethiol (376 mg, 2.36 mmol),tert-butyl[4-(chloromethyl)-1,3-thiazol-2-yl]carbamate (391 mg, 1.57mmol) and K₂CO₃ (1.08 g, 3.45 mmol) in DMF (10 ml).

¹H NMR (300 MHz, acetone-d₆) δ 10.18 (br. s., 1H), 7.17 (d, J=8.21 Hz,1H), 6.79 (d, J=2.34 Hz, 1H), 6.62 (s, 1H), 6.51 (dd, J=2.05, 8.20 Hz,1H), 5.30 (br. s., 1H), 3.88 (s, 2H), 1.53 (s, 9H).

Compound 11tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}carbamate

Following General Procedure B, the title compound (380 mg, 54%) wasprepared fromtert-butyl(4-{[(2-amino-4-chlorophenyl)thio]methyl}-1,3-thiazol-2-yl)carbamate(640 mg, 1.72 mmol) and 1-benzofuran-2-sulfonyl chloride (372 mg, 1.72mmol) in pyridine (5 ml).

¹H NMR (300 MHz, acetone-d₆) δ 11.20 (br. s., 1H), 9.82 (br. s., 1H),7.78 (d, J=7.91 Hz, 2H), 7.67 (d, J=2.34 Hz, 1H), 7.62 (s, 1H),7.45-7.60 (m, 3H), 7.31-7.43 (m, 1H), 7.07-7.22 (m, 1H), 6.77 (s, 1H),3.93 (s, 2H), 1.55 (s, 9H).

General Procedure E Compound 12N-(2-{[(2-amino-1,3-thiazol-4-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

A solution oftert-butyl{4-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}carbamateCompound 11 (62 mg, 0.11 mmol), TFA (0.2 ml) in CH₂Cl₂ (1 ml) wasstirred overnight. The solvent was removed in vacuo and the crudeproduct was purified by column chromatography on silica gel (50% ethylacetate in hexane) to afford the title compound (45 mg, 88%).

¹H NMR (600 MHz, acetone-d₆) δ 8.78 (br. s., 1H), 7.77 (d, J=7.92 Hz,0H), 7.55-7.66 (m, 3H), 7.45-7.55 (m, 2H), 7.29-7.41 (m, 1H), 7.17 (dd,J=2.20, 8.36 Hz, 1 H), 6.33 (s, 1H), 3.90 (s, 2H).

Compound 134-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure B and C, the title compound was preparedfrom 5-chloro-2-(methylthio)aniline and4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.

¹H NMR (300 MHz, CD₃OD) δ 8.07 (s, 1H), 7.96 (d, J=8.50 Hz, 1H), 7.82(d, J=8.21 Hz, 1H), 7.76 (d, J=8.50 Hz, 1H), 7.41 (d, J=7.91 Hz, 1H),7.07 (s, 1H), 2.83 (s, 3H).

General Procedure F Intermediate 5N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide]

To a solution of 2,2′-dithiobis(5-chloroaniline) (CAS 29124-55-8)(1.59g, 5.0 mmol) in pyridine (20 ml) was added4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (2.76 g, 10.0mmol) and the reaction was stirred at room temperature for 16 h.Additional 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (2.76g, 10.0 mmol) and pyridine (20 ml) was added, and the reaction wasstirred for 20 h. The mixture was concentrated in vacuo and H₂O wasadded. A gum-like semi-solid was formed. After decanting H₂O, thesemi-solid was rinsed with H₂O (×2), taken in EtOAc, extracted with 1MHCl (×2), washed with H₂O, brine, dried over Na₂SO₄, and concentrated invacuo to give a brown thick syrup (6.5 g). To a solution of the crudesyrup in methanol (100 ml) was added 4M NaOH (12 ml), and the mixturewas heated at 100° C. for 15 min, cooled to room temperature, quenchedslowly with 1M HCl (˜50 ml) with stirring and cooling to pH 4-5. Thevolume of the resulting suspension was reduced in vacuo, followed byextraction with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄, and concentrated in vacuo. The crude solid containingsulfonic acid was pulverized in saturated NaHCO₃, and filtered, rinsedwith minimal amount of diethyl ether to yield the title compound as anoff-white solid (3.11 g).

¹H NMR (600 MHz, CD₃OD) δ 8.08 (d, J=2.05 Hz, 2H), 7.93 (dd, J=2.20,8.36 Hz, 2H), 7.81 (d, J=8.51 Hz, 2H), 7.22 (d, J=2.05 Hz, 2H),7.18-7.20 (m, 2H), 7.10 (d, J=8.51 Hz, 2H).

Compound 144-chloro-N-[5-chloro-2-(ethylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide

To a solution ofN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide]Intermediate 5 (0.32 g, 0.40 mmol) in CH₂Cl₂ (10 ml) was added saturatedaqueous NaHCO₃ (1.0 ml), polymer-bound triphenylphosphine (˜3 mmol/gtriphenylphosphine loading, 0.27 g, 0.80 mmol), and ethyl iodide (64 μl,0.80 mmol). The reaction was stirred at room temperature for 2 h and wasdiluted with EtOAc, filtered, and washed with brine, dried over Na₂SO₄,and concentrated. The residue was purified by column chromatography onsilica gel (0→25% ethyl acetate in hexane) to yield the title compoundas a yellow syrup (204 mg, 59%).

¹H NMR (600 MHz, CDCl₃) δ 8.12 (d, J=2.35 Hz, 1H), 7.88 (dd, J=2.35,8.22 Hz, 1H), 7.82 (br. s., 1H), 7.64 (d, J=2.35 Hz, 1H), 7.59 (d,J=8.51 Hz, 1H), 7.32 (d, J=8.22 Hz, 1H), 7.06 (dd, J=2.20, 8.36 Hz, 1H),2.60 (q, J=7.34 Hz, 2H), 1.10 (t, J=7.34 Hz, 3H).

Compound 154-chloro-N-[5-chloro-2-(ethylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure C, the title compound was prepared from4-chloro-N-[5-chloro-2-(ethylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide.

¹H NMR (600 MHz, CD₃OD) δ 8.15 (d, J=2.35 Hz, 1H), 8.00 (dd, J=2.20,8.36 Hz, 1H), 7.72 (d, J=8.51 Hz, 1H), 7.44 (d, J=8.51 Hz, 1H), 7.27 (d,J=2.05 Hz, 1H), 7.01 (dd, J=2.05, 8.51 Hz, 1H), 3.10-3.18 (m, 1H),2.89-2.97 (m, 1H), 1.11 (t, J=7.34 Hz, 3H).

Intermediate 6 ethyl6-[(tert-butoxycarbonyl)amino]pyridine-2-carboxylate

A mixture of ethyl 6-aminopyridine-2-carboxylate (1.57 g, 9.43 mmol),DMAP (1.12 g, 9.18 mmol), and di-tert-butyl dicarbonate (2.46 g, 11.3mmol) in THF (45 ml) was heated at 60° C. for 16 h. The solvent wasremoved and the residue was purified by chromatography on silica gel(10→15% ethyl acetate in hexane) to yield the title compound as a whitesolid (2.50 g, 100%).

Intermediate 7 tert-butyl[6-(chloromethyl)pyridin-2-yl]carbamate

To a solution of ethyl6-[(tert-butoxycarbonyl)amino]pyridine-2-carboxylate (456 mg, 1.71 mmol)in anhydrous ethanol (20 ml) was added pulverized CaCl₂ (395 mg, 3.42mmol). The suspension was stirred and cooled to 0° C. and NaBH₄ (325 mg,8.55 mmol) was added slowly. The reaction was stirred at 0° C. for 2 h,quenched with water, and extracted with CHCl₃ (×3). The combined organiclayer was dried over Na₂SO₄ and concentrated. The residue was purifiedby column chromatography on silica gel (30→50% ethyl acetate in hexane)to yield a colorless syrup (308 mg) as a mixture containingtert-butyl[6-(hydroxymethyl)pyridin-2-yl]carbamate as the majorcomponent (˜4:1 ratio). To a solution of the above mixture in CH₂Cl₂ (10ml) was added pyridine (144 μl, 1.79 mmol) and SOCl₂ (120 μl, 1.65mmol). The reaction was stirred at room temperature for 4 h, quenchedwith water and saturated Na₂CO₃, and extracted with CHCl₃. The combinedorganic layer was dried over Na₂SO₄ and concentrated. The residue waspurified by column chromatography on silica gel (10% ethyl acetate inhexane) to yield the title compound as a colorless syrup (208 mg, 50%over 2 steps).

Intermediate 8N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide)

Following General Procedure F, the title compound was prepared from2,2′-dithiobis(5-chloroaniline) and 1-benzofuran-2-sulfonyl chloride.

¹H NMR (600 MHz, CD₃OD) δ 7.72 (d, J=7.92 Hz, 2H), 7.55 (dd, J=0.59,8.51 Hz, 2H), 7.48 (s, 2H), 7.32-7.37 (m, 4H), 7.22 (d, J=2.05 Hz, 2H),6.99-7.02 (m, 2H), 6.96-6.99 (m, 2H).

General Procedure G Compound 16tert-Tutyl{6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate

To a solution ofN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide)(271 mg, 0.40 mmol) in CH₂Cl₂ (4 ml) and dioxane (4 ml) was addedsaturated aqueous NaHCO₃ (4 ml), polymer-bound triphenylphosphine (˜3mmol/g triphenylphosphine loading, 0.40 g, 1.20 mmol),tert-butyl[6-(chloromethyl)pyridin-2-yl]carbamate (195 mg, 0.80 mmol),and tetrabutylammonium iodide (30 mg, 0.08 mmol). The reaction wasstirred at room temperature for 4 h and was diluted with EtOAc,filtered, and washed with brine, dried over Na₂SO₄, and concentrated.The residue was purified by column chromatography on silica gel (10→15%ethyl acetate in hexane) to yield the title compound as a yellow solid(260 mg, 59%).

¹H NMR (600 MHz, CD₃OD) δ 7.74 (d, J=8.22 Hz, 1H), 7.70 (d, J=7.63 Hz,1H), 7.50-7.57 (m, 2H), 7.44-7.50 (m, 2H), 7.41 (s, 1H), 7.31-7.36 (m,2H), 7.09 (d, J=8.22 Hz, 1H), 6.65 (d, J=7.34 Hz, 1H), 3.88 (s, 2H),1.54 (s, 9H).

Compound 17N-(2-{[(6-aminopyridin-2-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure E, the title compound (33 mg, 78%) wasprepared fromtert-butyl{6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.

¹H NMR (600 MHz, CD₃OD) δ 7.63 (d, J=7.92 Hz, 1H), 7.58 (d, J=2.35 Hz,1H), 7.40-7.44 (m, 1H), 7.35-7.40 (m, 2H), 7.31-7.35 (m, 2H), 7.26 (ddd,J=0.88, 7.04, 7.92 Hz, 1H), 6.95 (dd, J=2.35, 8.22 Hz, 1H), 6.55 (d,J=8.51 Hz, 1H), 6.31 (d, J=7.04 Hz, 1H), 3.78 (s, 2H).

Compound 18tert-butyl{6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]pyridin-2-yl}carbamate

Following General Procedure C, the title compound (98 mg, 91%) wasprepared fromtert-butyl{6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.

¹H NMR (600 MHz, CD₃OD) δ 7.67 (d, J=8.22 Hz, 1H), 7.64 (d, J=7.04 Hz,1H), 7.47 (d, J=2.05 Hz, 1H), 7.42-7.46 (m, 1H), 7.36-7.39 (m, 1H),7.29-7.33 (m, 1H), 7.22-7.26 (m, 2H), 7.09 (d, J=8.22 Hz, 1H), 6.77 (dd,J=1.91, 8.36 Hz, 1H), 6.68 (d, J=7.34 Hz, 1H), 4.59 (d, J=12.62 Hz, 1H),4.16 (d, J=12.62 Hz, 1H), 1.52 (s, 9H).

Compound 19N-(2-{[(6-aminopyridin-2-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure E, the title compound (71 mg, 91%) wasprepared fromtert-butyl{6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]pyridin-2-yl}carbamate.

¹H NMR (300 MHz, CD₃OD) δ 7.65 (d, J=7.91 Hz, 1H), 7.52-7.62 (m, 1H),7.50 (d, J=1.47 Hz, 1H), 7.39-7.46 (m, 1H), 7.29-7.38 (m, 2H), 7.20-7.29(m, 2H), 6.89 (dd, J=1.47, 8.50 Hz, 1H), 6.79 (d, J=8.79 Hz, 1H), 6.44(d, J=7.03 Hz, 1H), 4.60 (d, J=13.48 Hz, 1H), 4.25 (d, J=13.19 Hz, 1H).

Compound 20tert-butyl{6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]pyridin-2-yl}carbamate

Following General Procedure D, the title compound (60 mg, 56%) wasprepared fromtert-butyl{6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.

¹H NMR (300 MHz, CD₃OD) δ 7.79 (d, J=1.76 Hz, 1H), 7.65 (d, J=7.62 Hz,1H), 7.55 (d, J=8.50 Hz, 1H), 7.44 (s, 1H), 7.18-7.40 (m, 5H), 6.72 (dd,J=1.76, 8.50 Hz, 1H), 6.60 (d, J=7.33 Hz, 1H), 4.97 (s, 2H), 1.51 (s,9H).

Compound 21N-(2-{[(6-aminopyridin-2-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure E, the title compound (47 mg, 94%) wasprepared fromtert-butyl{6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]pyridin-2-yl}carbamate.

¹H NMR (300 MHz, CD₃OD) δ 7.73 (d, J=2.05 Hz, 1H), 7.66 (d, J=7.62 Hz,1H), 7.52 (d, J=8.79 Hz, 1H), 7.20-7.44 (m, 4H), 7.14 (t, J=7.77 Hz,1H), 6.73 (dd, J=1.76, 8.50 Hz, 1H), 6.48 (d, J=8.20 Hz, 1H), 6.28 (d,J=7.33 Hz, 1H), 4.91 (s, 2H).

Compound 22 tert-butyl3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1H-pyrazole-1-carboxylate

Following General Procedure G, the title compound (206 mg, 36%) wasprepared fromN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide)and tert-butyl 3-(bromomethyl)-1H-pyrazole-1-carboxylate.

¹H NMR (600 MHz, CDCl₃) δ 8.30 (br. s., 1H), 7.93 (d, J=2.64 Hz, 1H),7.62-7.67 (m, 2H), 7.47-7.52 (m, 1H), 7.42-7.45 (m, 1H), 7.41 (s, 1H),7.34 (d, J=8.22 Hz, 1H), 7.28-7.32 (m, 1H), 7.00 (dd, J=2.20, 8.36 Hz,1H), 6.03 (d, J=2.64 Hz, 1H), 3.88 (s, 2H), 1.64 (s, 9H).

Compound 23N-{5-chloro-2-[(1H-pyrazol-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure E, the title compound (15 mg, 66%) wasprepared from tert-butyl3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1H-pyrazole-1-carboxylate.

¹H NMR (600 MHz, CD₃OD) δ 7.70 (d, J=7.92 Hz, 1H), 7.51-7.55 (m, 1H),7.45-7.50 (m, 2H), 7.37-7.44 (m, 2H), 7.34 (t, J=7.19 Hz, 1H), 7.25-7.31(m, 1H), 7.11 (dd, J=1.76, 8.22 Hz, 1H), 5.88 (br. s., 1H), 3.89 (s,2H).

General Procedure H Intermediate 93-[(2-amino-4-chlorophenyl)thio]-N,N-dimethylpropanamide

A mixture of 2-amino-4-chlorobenzenethiol (327 mg, 2.05 mmol),N,N-dimethylacrylamide (203 mg, 2.05 mmol) and HOAc (0.5 ml) in CH₂Cl₂(5 ml) was stirred at room temperature for 3 days. The reaction wasquenched with NaHCO₃ (aq.) and then extracted with CH₂Cl₂ (2×10 ml).Theorganic layer was washed with water and brine and concentrated in vacuo.The crude product was purified by chromatography on silica gel (50%ethyl acetate in hexane) to yield the title compound (284 mg, 54%).

¹H NMR (300 MHz, CD₃OD) δ 7.26 (d, J=8.21 Hz, 1H), 6.76 (d, J=2.05 Hz,1H), 6.56 (dd, J=2.34, 8.20 Hz, 1H), 2.85-3.02 (m, 8H), 2.57 (t, J=7.03Hz, 2H).

Compound 243-{[4-Chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylpropanamide

Following General Procedure B and C, the title compound (280 mg) wasprepared from 3-[(2-amino-4-chlorophenyl)thio]-N,N-dimethylpropanamide(284 mg, 1.11 mmo).

¹H NMR (600 MHz, CD₃OD) δ 8.16 (d, J=1.76 Hz, 1H), 8.00 (dd, J=2.05,8.22 Hz, 1H), 7.75 (d, J=8.51 Hz, 1H), 7.57 (d, J=8.51 Hz, 1H), 7.32 (s,1H), 7.21 (d, J=7.92 Hz, 1H), 3.26 (br. s., 1H), 3.18 (br. s., 1H), 3.02(s, 3H), 2.95 (s, 3H), 2.83-2.91 (m, 1H), 2.62-2.76 (m, 1H).

Compound 25tert-Butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]-1,3-thiazol-2-yl}carbamate

Following General Procedure C, tert-Butyl(4-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)thiazol-2-yl)carbamate(138mg, 0.25 mmol) was oxidized to the title compound (97 mg, 68%).

1H NMR (600 MHz, acetone-d6) δ 10.43 (br. s., 1H), 7.75-7.84 (m, 2H),7.66 (d, J=2.05 Hz, 1H), 7.62 (dd, J=0.88, 8.51 Hz, 1H), 7.50 (ddd,J=1.32, 7.26, 8.44 Hz, 1H), 7.32-7.41 (m, 1H), 7.11-7.24 (m, 2H), 6.74(s, 1H), 4.47 (d, J=12.91 Hz, 1H), 4.37 (d, J=12.91 Hz, 1H), 1.50 (s,9H).

Compound 26N-(2-{[(2-amino-1,3-thiazol-4-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure E,tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]-1,3-thiazol-2-yl}carbamate(87 mg, 0.153 mmol) was de-Boc to give the title compound (58 mg, 82%).

1H NMR (600 MHz, acetone-d6) δ 10.43 (br. s., 1H), 7.75-7.84 (m, 2H),7.66 (d, J=2.05 Hz, 1H), 7.62 (dd, J=0.88, 8.51 Hz, 1H), 7.50 (ddd,J=1.32, 7.26, 8.44 Hz, 1H), 7.32-7.41 (m, 1H), 7.11-7.24 (m, 2H), 6.74(s, 1H), 4.47 (d, J=12.91 Hz, 1H), 4.37 (d, J=12.91 Hz, 1H), 1.50 (s,9H).

Compound 27tert-Butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]-1,3-thiazol-2-yl}carbamate

Following General Procedure D, the title compound (112 mg, 90%) wasprepared from tert-Butyl(4-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)thiazol-2-yl)carbamate(117 mg, 0.212 mmol).

1H NMR (600 MHz, acetone-d6) δ 7.80 (d, J=7.92 Hz, 2H), 7.78 (d, J=1.76Hz, 1H), 7.67 (d, J=8.51 Hz, 1H), 7.59 (d, J=7.92 Hz, 1H), 7.50 (t,J=7.63 Hz, 1H), 7.37 (t, J=7.48 Hz, 1H), 6.99 (s., 1H), 4.70 (s., 2H),1.53 (s, 9H)

1H NMR (600 MHz, acetone-d6) δ 7.80 (d, J=7.92 Hz, 2H), 7.67 (d, J=8.51Hz, 1H), 7.60 (br. s., 1H), 7.50 (t, J=7.63 Hz, 1H), 7.33-7.41 (m, 1H),6.99 (br. s., 1H), 4.70 (br. s., 2H), 1.53 (s, 9H).

Compound 28N-(2-{[(2-amino-1,3-thiazol-4-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure E, the title compound (54 mg, 86%) wasprepared fromtert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]-1,3-thiazol-2-yl}carbamate(77 mg, 0.153 mmol).

1H NMR (600 MHz, acetone-d6) δ 7.74-7.85 (m, 2H), 7.68 (d, J=2.35 Hz,1H), 7.64 (dd, J=0.88, 8.51 Hz, 1H), 7.53 (ddd, J=1.32, 7.19, 8.51 Hz,1H), 7.39 (ddd, J=0.88, 7.26, 8.00 Hz, 1H), 7.16-7.24 (m, 2H), 6.74 (s,1H), 4.32-4.46 (m, 2H), 1.47-1.55 (m, 9H).

Intermediate 105-chloro-2-(((5-nitro-1H-pyrazol-3-yl)methyl)thio)aniline

(5-Nitro-1H-pyrazol-3-yl)methanol (524 mg, 3.66 mmol) was first treatedwith SOCl₂ (3 ml) in CH₂Cl₂ (5 ml) at 35° C. for 2 hrs. The solvent wasremoved to get a crude 3-(chloromethyl)-5-nitro-1H-pyrazole. Thenfollowing General Procedure A, the title compound (515 mg, 49%) wasprepared from 2-amino-4-chlorobenzenethiol (161 mg, 1.01 mmol), crude3-(chloromethyl)-5-nitro-1H-pyrazole, K₂CO₃ (468 mg, 3.39 mmol) in DMF(3 ml).

1H NMR (600 MHz, CD₃OD) δ 7.05 (d, J=8.22 Hz, 1H), 6.77 (d, J=2.35 Hz,1H), 6.60 (s, 1H), 6.49 (dd, J=2.05, 8.22 Hz, 1H), 3.95 (s, 2H).

Compound 29 N-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure B, the title compound (580 mg, 71%) wasprepared from 5-chloro-2-(((5-nitro-1H-pyrazol-3-yl)methyl)thio)aniline(503 mg, 1.77 mmol) and benzofuran-2-sulfonyl chloride (384 mg, 1.77mmol) in pyridine (5 ml).

1H NMR (600 MHz, CD₃OD) δ 7.70-7.73 (m, 1H), 7.53-7.56 (m, 1H), 7.49 (d,J=1.47 Hz, 1H), 7.47-7.49 (m, 1H), 7.47 (d, J=1.17 Hz, 1H), 7.45 (d,J=2.35 Hz, 1H), 7.44 (d, J=0.88 Hz, 1H), 7.35 (ddd, J=0.88, 7.26, 8.00Hz, 1H), 7.15 (dd, J=2.35, 8.22 Hz, 1H), 6.42 (s, 1H), 3.97 (s, 2H).

Compound 30N-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (155 mg, 61%) wasprepared fromN-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide(245 mg, 0.528 mmol).

1H NMR (600 MHz, CD₃OD) δ 7.67 (dt, J=0.77, 7.56 Hz, 1H), 7.42-7.45 (m,2H), 7.35 (td, J=1.32, 7.85 Hz, 1H), 7.24-7.29 (m, 2H), 7.09 (d, J=8.22Hz, 1H), 6.85 (d, J=8.22 Hz, 1H), 6.33 (s, 1H),4.61 (d, J=14.09 Hz, 1H),4.48 (d, J=14.09 Hz, 1H).

General Procedure I Compound 31N-(2-{[(5-amino-1H-pyrazol-3-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

N-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide (77 mg,0.166 mmol) was reduced to the title compound under H₂ balloon in thepresent of Pd/C (10% wt, 18 mg) in MeOH (3 ml).

1H NMR (600 MHz, CD₃OD) δ 7.70 (d, J=7.92 Hz, 1H), 7.52-7.56 (m, 2H),7.48 (ddd, J=1.17, 7.12, 8.44 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 1H), 7.34(t, J=7.48 Hz, 1H), 7.28 (d, J=8.51 Hz, 1H), 7.11 (dd, J=2.20, 8.36 Hz,1H), 3.74 (s, 2H).

Compound 32N-(2-{[(5-amino-1H-pyrazol-3-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following the General Procedure I, the title compound (39 mg, 91%) wasreduced fromN-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide(46 mg, 0.096 mmol).

1H NMR (600 MHz, CD₃OD) δ 7.91-7.99 (m, 1H), 7.67-7.72 (m, 1H),7.56-7.62 (m, 1H), 7.50-7.55 (m, 1H), 7.41-7.48 (m, 2H), 7.29-7.40 (m,2H), 7.13 (dd, J=1.91, 8.36 Hz, 1H), 4.55 (d, J=13.79 Hz, 1H), 4.05 (d,J=13.79 Hz, 1H)

Compound 33N-(2-{[(5-amino-1H-pyrazol-3-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D and H, the title compound (27 mg) wasprepared fromN-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.69-7.74 (m, 2H), 7.62-7.58 (m, 3H), 7.51(dd, J=0.59, 8.51 Hz, 1H), 7.44 (ddd, J=1.17, 7.12, 8.44 Hz, 1H),7.26-7.35 (m, 1H), 7.09 (dd, J=1.91, 8.66 Hz, 1H), 4.59 (s, 2H).

Intermediate 11 1-propyl-1H-imidazole-4-carbaldehyde

To a suspension of NaH (95%, 231 mg, 9.18 mmol) in THF (20 ml) was added4-imidazole carboxaldehyde (588 mg, 6.12 mmol) under ice cooling. Themixture was refluxed for 2 hours under nitrogen atmosphere. The mixturewas cooled to room temperature and 1-iodopropane (5 ml) was added to themixture and then refluxed for another 2 hours. The mixture was cooleddown to rt and quenched with water. The solution was extracted withEtOAc (2×50 ml), washed with brine, dried over Na₂SO₄, concentrated invacuo. The crude product was purified by column chromatography on silicagel (0-10% MeOH in CH₂Cl₂) to give the title compound (487 mg, 58%).

1H NMR (600 MHz, CD₃OD) δ 9.73 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 4.07(t, J=7.04 Hz, 2H), 1.73-1.92 (m, 2H), 0.93 (t, J=7.34 Hz, 3H).

Intermediate 12 (1-propyl-1H-imidazol-4-yl)methanol

To a solution of LAH (2.0 M in THF, 1.9 ml, 3.882 mmol) in THF (10 ml)was added dropwise a solution of 1-propyl-1H-imidazole-4-carbaldehyde(487 mg, 3.529 mmol) in THF (4 ml) at 0° C. After stirred at 0° C. for 5min, water (0.2 ml), 15% NaOH (0.2 ml) was added dropwise to thereaction mixture under 0° C. The mixture was further stirred at roomtemperature for 2 hours. MgSO₄ was added to the mixture and the solidwas filtered away and the filtrate was concentrated in vacuo to get ayellow oil and used without further purification.

1H NMR (600 MHz, CD₃Cl₃) δ 7.42 (s, 1H), 6.86 (s, 1H), 4.59 (s, 2H),3.87 (t, J=7.04 Hz, 2H), 1.73-1.82 (m, 2H), 0.93 (t, J=7.34 Hz, 3H).

Intermediate 135-chloro-2-(((1-propyl-1H-imidazol-4-yl)methyl)thio)aniline

(1-propyl-1H-imidazol-4-yl)methanol (535 mg, 3.11 mmol) was firsttreated with SOCl₂ (3 ml) in CH₂Cl₂ (5 ml) at 35° C. for 2 hrs. Thesolvent was removed to get a crude4-(chloromethyl)-1-propyl-1H-imidazole. Then following General ProcedureA, the title compound (587 mg, 67%) was prepared from2-amino-4-chlorobenzenethiol (744 mg, 4.66 mmol),4-(chloromethyl)-1-propyl-1H-imidazole, K₂CO₃ (2.1g, 15.54 mmol) in DMF(10 ml).

1H NMR (600 MHz, CDCL₃) δ 7.38 (s, 1H), 7.17 (d, J=8.22 Hz, 1H), 6.67(d, J=2.05 Hz, 1H), 6.57 (dd, J=2.20, 8.07 Hz, 1H), 6.51 (s, 1H), 3.85(s, 2H), 3.79 (t, J=7.04 Hz, 2H), 1.67-1.76 (m, 2H), 0.88 (t, J=7.34 Hz,3H).

Compound 34N-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure B, the title compound (463 mg, 48%) wasprepared from5-chloro-2-(((1-propyl-1H-imidazol-4-yl)methyl)thio)aniline (587 mg,2.082 mmol) and benzofuran-2-sulfonyl chloride (451 mg, 2.082 mmol) inpyridine (10 ml).

1H NMR (600 MHz, CD₃OD) δ 7.71 (dt, J=1.03, 7.92 Hz, 1H), 7.57 (d,J=1.17 Hz, 1H), 7.52-7.55 (m, 1H), 7.44-7.51 (m, 2H), 7.42 (d, J=0.88Hz, 1H), 7.34 (td, J=1.03, 7.56 Hz, 1H), 7.27 (d, J=8.22 Hz, 1H), 7.07(dd, J=2.35, 8.51 Hz, 1H), 6.44-6.51 (m, 1H), 3.75-3.81 (m, 4H), 1.63(dquin, J=7.19, 7.34 Hz, 2H), 0.74-0.82 (m, 3H).

Compound 35N-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (148 mg, 75%) wasprepared fromN-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 8.46 (s, 1H), 7.70 (dd, J=1.47, 8.22 Hz, 1H),7.49 (dd, J=0.88, 8.51 Hz, 1H), 7.38-7.43 (m, 2H), 7.35 (d, J=0.88 Hz,1H), 7.30 (ddd, J=1.03, 7.19, 7.92 Hz, 1H), 7.12 (d, J=8.51 Hz, 1H),6.91 (dd, J=1.91, 8.36 Hz, 1H), 6.80 (s, 1H), 4.57 (d, J=14.38 Hz, 1H),4.43 (d, J=14.09 Hz, 1H), 3.84-3.99 (m, 2H), 1.57-1.71 (m, 2H), 0.81 (t,J=7.34 Hz, 3H).

Compound 36N-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound (115 mg, 60%) wasprepared fromN-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.

1H NMR (300 MHz, CD₃OD) δ 7.82 (s, 1H), 7.71 (dd, J=1.32, 7.77 Hz, 1H),7.67 (d, J=2.05 Hz, 1H), 7.55 (d, J=8.50 Hz, 1H), 7.44-7.50 (m, 2H),7.41 (td, J=1.32, 7.69 Hz, 1H), 7.25-7.35 (m, 1H), 6.85 (dd, J=2.05,8.79 Hz, 1H), 6.76 (s, 1H), 4.57 (s, 2H),3.74 (t, J=7.03 Hz, 2H), 1.54(quind, J=6.89, 7.07 Hz, 2H), 0.69 (t, J=7.47 Hz, 3H).

Intermediate 14 tert-butyl(4-(hydroxymethyl)pyridin-2-yl)carbamate

A solution of (2-aminopyridin-4-yl)methanol (547 mg, 4.408 mmol),di-tert-butyl dicarbonate (1.25 g, 5.730 mmol), in t-BuOH (20 ml) wasstirred at room temperature overnight. The solvent was removed and addedethyl acetate, filtered away the solid and the filtrate was concentratedin vacuo. The residue was purified by column chromatography (10% MeOH inCH₂Cl₂) to give the title compound as a white solid (703 mg, 71%).

1H NMR (600 MHz, CDCl₃) δ 8.18 (d, J=5.28 Hz, 1H), 8.00 (s, 1H),6.92-7.10 (m, 1H), 4.75 (s, 2H), 1.32-1.66 (m, 9H).

Intermediate 15tert-butyl(4-(((2-amino-4-chlorophenyl)thio)methyl)pyridin-2-yl)carbamate

tert-butyl(4-(hydroxymethyl)pyridin-2-yl)carbamate (600 mg, 2.679 mmol)was first treated with SOCl₂ (3 ml) in CH₂Cl₂ (5 ml) at rt for 2 hrs.The solvent was removed to get a crudetert-butyl(4-(chloromethyl)pyridin-2-yl)carbamate. Then followingGeneral Procedure A, the title compound (667 mg, 68%) was prepared from2-amino-4-chlorobenzenethiol (641 mg, 4.019 mmol), K₂CO₃ (1.8 g, 13.39mmol) in DMF (20 ml).

1H NMR (600 MHz, CDCl₃) δ 9.83 (br. s., 1H), 8.20 (d, J=4.70 Hz, 1H),7.85 (s, 1H), 6.92-7.18 (m, 1H), 6.60-6.75 (m, 2H), 6.55 (dd, J=2.05,8.22 Hz, 1H), 4.42 (br. s., 2H), 3.78 (s, 2H), 1.54 (s, 9H).

Compound 37tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate

Following General Procedure B, the title compound (555 mg, 56%) wasprepared fromtert-butyl(4-(((2-amino-4-chlorophenyl)thio)methyl)pyridin-2-yl)carbamate(667mg, 1.827 mmol) and benzofuran-2-sulfonyl chloride (396 mg, 1.827 mmol)in pyridine (10 ml).

1H NMR (600 MHz, CD₃OD) δ 7.99 (d, J=4.99 Hz, 1H), 7.64-7.73 (m, 2H),7.59 (d, J=1.17 Hz, 1H), 7.50-7.55 (m, 1H), 7.42-7.50 (m, 2H), 7.30-7.39(m, 1H), 7.15 (dd, J=1.03, 8.36 Hz, 1H), 6.96-7.05 (m, 1H), 6.56 (d,J=5.28 Hz, 1H), 3.77 (s, 2H), 1.48-1.61 (m, 9H).

Compound 38N-(2-{[(2-aminopyridin-4-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure E, the title compound (76 mg, 100%) wasprepared fromtert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate(96 mg, 0.176 mmol).

1H NMR (600 MHz, CD₃OD) δ 7.72-7.76 (m, 2H), 7.65 (d, J=6.46 Hz, 2H),7.58 (dd, J=0.73, 8.36 Hz, 1H), 7.46-7.53 (m, 2H), 7.42 (d, J=2.05 Hz,1H), 7.37 (td, J=1.03, 7.56 Hz, 1H), 7.31 (d, J=8.51 Hz, 1H), 7.16 (dd,J=2.35, 8.51 Hz, 1H), 6.64 (dd, J=1.61, 6.60 Hz, 1H), 6.50 (s, 1H), 3.90(s, 2H).

Compound 39tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]pyridin-2-yl}carbamate

Following General Procedure D, the title compound (49 mg) was preparedfromtert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.

1H NMR (600 MHz, CD₃OD) δ 7.93 (d, J=6.75 Hz, 1H), 7.78 (s, 1H), 7.73(d, J=2.05 Hz, 1H), 7.63 (d, J=7.63 Hz, 1H), 7.41 (d, J=8.80 Hz, 1H),7.33 (s, 1H), 7.29 (d, J=3.81 Hz, 1H), 7.23 (dt, J=3.96, 7.92 Hz, 2H),6.85 (dd, J=2.20, 6.60 Hz, 1H), 6.68 (d, J=7.92 Hz, 1H), 4.56 (br. s.,2H), 1.47 (s, 9H).

Compound 40tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]-1-oxidopyridin-2-yl}carbamate

Following General Procedure D, the title compound (82 mg) was preparedfromtert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.

1H NMR (600 MHz, CD₃OD) δ 8.22 (d, J=6.46 Hz, 1H), 7.96 (s, 1H), 7.76(d, J=16.73 Hz, 1H), 7.60-7.68 (m, 1H), 7.43 (d, J=8.51 Hz, 1H), 7.37(s, 1H), 7.31 (br. s., 1H), 7.21-7.27 (m, 1H), 7.09 (d, J=6.46 Hz, 1H),6.85 (d, J=6.75 Hz, 1H), 6.72 (d, J=7.63 Hz, 1H), 4.60 (br. s., 2H),1.55 (s, 9H).

Compound 41N-(2-{[(2-aminopyridin-4-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure E, the title compound (32 mg, 100%) wasprepared fromtert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]pyridin-2-yl}carbamate.

1H NMR (600 MHz, acetone-d6) δ 7.74-7.85 (m, 3H), 7.61-7.70 (m, 2H),7.52-7.58 (m, 1H), 7.45 (td, J=1.17, 7.92 Hz, 1H), 7.28-7.38 (m, 1H),7.09 (dd, J=2.05, 8.51 Hz, 1H), 6.88 (s, 1H), 6.57-6.66 (m, 1H), 4.89(s, 2H).

Compound 42N-(2-{[(2-amino-1-oxidopyridin-4-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure E, the title compound (43 mg, 67%) wasprepared fromtert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]-1-oxidopyridin-2-yl}carbamate(77 mg, 0.130 mmol).

1H NMR (600 MHz, acetone-d6) δ 8.07 (d, J=4.70 Hz, 3H), 7.76-7.81 (m,2H), 7.74 (s, 1H), 7.64 (d, J=8.51 Hz, 1H), 7.58 (d, J=8.51 Hz, 1H),7.46-7.49 (m, 1H), 7.32-7.37 (m, 1H), 7.15 (dd, J=1.32, 8.36 Hz, 1H),6.94 (br. s., 1H), 6.52 (d, J=4.99 Hz, 1H), 4.76 (s, 2H).

Compound 43N-(2-{[(2-aminopyridin-4-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure C and General Procedure E, the titlecompound (103 mg) was prepared fromtert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.

1H NMR (600 MHz, acetone-d6) δ 8.29 (br. s., 1H), 7.74 (dd, J=7.04,18.19 Hz, 2H), 7.40-7.61 (m, 4H), 7.25-7.37 (m, 2H), 7.05 (d, J=7.04 Hz,1H), 6.84 (s, 1H), 6.49 (d, J=6.16 Hz, 1H), 4.50 (d, J=12.62 Hz, 2H),4.40 (d, J=12.62 Hz, 1H).

Intermediate 16 3-((2-amino-4-chlorophenyl)thio)-N,N-dimethylpropanamide

The solution of 2-amino-4-chlorobenzenethiol (824 mg, 5.126 mmol),N,N-dimethylacrylamide (512 mg, 5.162 mmol), and HOAc (1 ml) in CH₂Cl₂(10 ml) was stirred at room temperature for 4 days. The solvent wasremoved and the residue was loaded on silica column and purified toyield a white solid (1.08 g, 83%).

1H NMR (600 MHz, CD₃OD) δ 7.26 (d, J=8.22 Hz, 1H), 6.76 (d, J=2.05 Hz,1H), 6.56 (dd, J=2.05, 8.22 Hz, 1H), 2.93-2.97 (m, 5H), 2.90 (s, 3H),2.58 (t, J=7.04 Hz, 2H).

Compound 443-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylpropanamide

Following General Procedure B and D, the title compound (73mg) wasprepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-dimethylpropanamide(104 mg, 0.405 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonylchloride (113 mg, 0.405 mmol).

1H NMR (600 MHz, CD₃OD) δ 8.31 (d, J=1.47 Hz, 1H), 8.12 (dd, J=1.76,8.51 Hz, 1H), 7.70 (dd, J=8.51, 18.49 Hz, 2H), 7.58 (s, 1H), 6.90 (s.,1H), 3.73 (br. s., 2H), 3.01 (s, 3H), 2.95 (s, 3H), 2.78 (t, J=6.75 Hz,2H).

Compound 453-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide

Following General Procedure B, the title compound (364 mg, 72%) wasprepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-dimethylpropanamide(300 mg, 1.167 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (248mg, 1.167 mmol) in pyridine (5 ml).

1H NMR (600 MHz, CD₃OD) δ 7.86 (td, J=6.02, 8.44 Hz, 1H), 7.38-7.45 (m,2H), 7.13-7.21 (m, 2H), 7.09 (tdd, J=0.88, 2.49, 8.44 Hz, 1H), 2.95-3.01(m, 5H), 2.93 (s, 3H), 2.56 (t, J=7.04 Hz, 2H).

Compound 463-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)sulfinyl]-N,N-dimethylpropanamide

Following General Procedure C, the title compound (130 mg, 88%) wasprepared from3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide.

1H NMR (600 MHz, CD₃OD) δ 7.90 (td, J=5.87, 8.51 Hz, 1H), 7.69 (d,J=8.51 Hz, 1H), 7.43 (dd, J=2.05, 8.51 Hz, 1H), 7.31 (d, J=2.05 Hz, 1H),7.20-7.27 (m, 1H), 7.11-7.17 (m, 1H), 3.24-3.29 (m, 1H), 3.12-3.20 (m,1H), 3.05(s, 3H), 2.93 (s, 3H), 2.85-2.92 (m, J=4.40 Hz, 1H), 2.72-2.80(m, J=6.46, 6.46, 17.02 Hz, 1H).

Compound 473-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)sulfonyl]-N,N-dimethylpropanamide

Following General Procedure D, the title compound (70 mg, 71%) wasprepared from3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide.

1H NMR (600 MHz, CD₃OD) δ 8.01-8.12 (m, 1H), 7.76 (d, J=8.51 Hz, 2H),7.49-7.60 (m, 2H), 6.95-7.24 (m, 3H), 3.72 (br. s., 2H), 3.01 (s, 3H),2.90 (s, 3H), 2.78 (t, J=7.04 Hz, 2H).

Compound 483-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide

Following General Procedure B, the title compound (476 mg, 75%) wasprepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-dimethylpropanamide(364 mg, 1.42 mmol) and 4-chloro-2-fluorobenzene-1-sulfonyl chloride(325 mg, 1.42 mmol) in pyridine (5 ml).

1H NMR (600 MHz, acetone-d6) δ 9.57 (br. s., 1H), 7.86 (t, J=8.07 Hz,1H), 7.50-7.56 (m, 2H), 7.45 (dd, J=1.91, 9.83 Hz, 1H), 7.40 (dd,J=1.91, 8.36 Hz, 1H), 7.17 (dd, J=2.35, 8.22 Hz, 1H), 2.94-3.01 (m, 5H),2.91 (s, 3H), 2.54 (t, J=6.46 Hz, 3H).

Compound 493-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]-N,N-dimethylpropanamide

Following General Procedure C, the title compound (90 mg, 55%) wasprepared from3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide.

1H NMR (600 MHz, CD₃OD) δ 7.78-7.90 (m, 1H), 7.48 (d, J=8.51 Hz, 1H),7.27-7.34 (m, 2H), 7.26 (d, J=2.05 Hz, 1H), 7.03 (d, J=7.92 Hz, 1H),3.43 (ddd, J=6.31, 9.02, 13.43 Hz, 1H), 3.16 (ddd, J=5.58, 9.10, 13.50Hz, 1H), 2.99 (s, 3H), 2.92 (s, 3H), 2.79-2.88 (m, J=6.46, 9.17, 16.07Hz, 1H), 2.52-2.64 (m, 1H).

Compound 503-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]-N,N-dimethylpropanamide

Following General Procedure D, the title compound (81 mg, 48%) wasprepared from3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide.

1H NMR (600 MHz, CD₃OD) δ 7.89-7.98 (m, 1H), 7.69 (d, J=8.51 Hz, 1H),7.46 (d, J=2.05 Hz, 1H), 7.20-7.30 (m, 2H), 6.76 (d, J=7.63 Hz, 1H),3.86 (t, J=7.19 Hz, 2H), 2.97 (s, 3H), 2.93 (s, 3H), 2.70 (t, J=7.34 Hz,2H).

Intermediate 17tert-butyl(5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl)carbamate

(5-amino-4H-1,2,4-triazol-3-yl)methanol (467 mg, 4.093 mmol),di-tert-butyl dicarbonate (1.16 g, 5.32 mmol), in t-BuOH (20 ml) wasstirred at room temperature overnight. The solvent was removed and addedethyl acetate, filtered away the solid and the filtrate was concentratedin vacuo. The residue was purified by column chromatography (10% MeOH inCH₂Cl₂) to give the title compound as a yellow oil (190 mg, 22%).

1H NMR (300 MHz, CD₃OD) δ 4.44 (s, 2H), 1.63 (s, 9H).

General Procedure J Intermediate 18tert-butyl(5-(((2-amino-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate

A solution oftert-butyl(5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl)carbamate (190 mg,0.888 mmol), 2-amino-4-chlorobenzenethiol (213 mg, 1.332 mmol), PPh3(466 mg, 1.776 mmol) and di-tert-butylazodicarboxylate (409 mg, 1.776mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 2 days. Thesolvent was then removed and the crude residues was loaded on silica gelcolumn to get the title compound.

1H NMR (600 MHz, CD₃OD) δ 7.18 (s, 1H), 6.73 (d, J=2.35 Hz, 1H), 6.49(dd, J=2.35, 8.22 Hz, 2H), 3.68 (s, 2H), 1.60 (s, 9H).

Intermediate 19tert-butyl(5-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate

Following General Procedure B, the title compound was prepared fromtert-butyl(5-(((2-amino-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate(330 mg, 0.925 mmol) and benzofuran-2-sulfonyl chloride (200 mg, 0.925mmol) in pyridine (2 ml).

1H NMR (600 MHz, CD₃OD) δ 7.69 (dd, J=0.88, 7.92 Hz, 1H), 7.45-7.57 (m,4H), 7.40 (s, 1H), 7.29-7.35 (m, 1H), 7.16 (dd, J=2.35, 8.22 Hz, 1H),3.70 (s, 2H), 1.61 (s, 9H).

Compound 51N-(2-{[(5-amino-4H-1,2,4-triazol-3-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure E, the title compound (13 mg) was preparedfromtert-butyl(5-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate.

1H NMR (600 MHz, CD₃OD) δ 7.71 (d, J=7.92 Hz, 1H), 7.55 (d, J=8.51 Hz,1H), 7.39-7.51 (m, 5H), 7.31-7.37 (m, 1H), 7.16 (d, J=7.04 Hz, 1H), 3.82(s, 2H).

Compound 52N-(2-{[(5-amino-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure C and E, the title compound (15 mg) wasprepared fromtert-butyl(5-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate.

1H NMR (600 MHz, CD₃OD) δ 7.75 (dd, J=1.17, 7.92 Hz, 1H), 7.57-7.64 (m,2H), 7.51-7.55 (m, 1H), 7.50 (d, J=0.88 Hz, 1H), 7.44 (dd, J=1.91, 8.36Hz, 1 H), 7.35-7.41 (m, 1H), 7.20 (d, J=2.05 Hz, 1H), 4.45 (d, J=14.09Hz, 1H), 4.24 (d, J=14.09 Hz, 1H).

Intermediate 20 5-chloro-2-((2-(pyridin-2-yl)ethyl)thio)aniline

2-(Pyridin-2-yl)ethanol (1 g, 8.12 mmol) was first treated with SOCl₂ (3ml) in CH₂Cl₂ (10 ml) at rt for 3 hrs. The solvent was removed to get acrude 2-(2-chloroethyl)pyridine. Then following General Procedure A, thetitle compound (1.69 g, 79%) was prepared from2-amino-4-chlorobenzenethiol (1.6 g, 9.74 mmol), K₂CO₃ (3.36 g, 24.36mmol) in DMF (20 ml).

1H NMR (600 MHz, CD₃OD) δ 8.39-8.42 (m, 1H), 7.73 (td, J=1.76, 7.63 Hz,1H), 7.28 (d, J=7.63 Hz, 1H), 7.23 (d, J=8.22 Hz, 2H), 6.75 (d, J=2.35Hz, 1H), 6.55 (dd, J=2.35, 8.22 Hz, 1H), 3.06-3.10 (m, 2H), 2.96-3.01(m, 2H).

Compound 53N-{5-chloro-2-[(2-pyridin-2-ylethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure B, the title compound was prepared from5-chloro-2-((2-(pyridin-2-yl)ethyl)thio)aniline (439 mg, 1.663 mmol) andbenzofuran-2-sulfonyl chloride (2×359 mg, 2×1.663 mmol) in pyridine (5ml).

1H NMR (600 MHz, CD₃OD) δ 8.54-8.62 (m, 1H), 7.85 (s, 1H), 7.71-7.78 (m,1H), 7.67 (dt, J=1.03, 7.92 Hz, 1H), 7.56 (d, J=2.35 Hz, 1H), 7.39-7.48(m, 2H), 7.36 (s, 1H), 7.27-7.32 (m, 2H), 7.15-7.22 (m, 2H), 2.98 (t,J=7.04 Hz, 2H), 2.74 (t, J=6.90 Hz, 2H).

Compound 54N-{5-chloro-2-[(2-pyridin-2-ylethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (45 mg, 79%) wasprepared fromN-{5-chloro-2-[(2-pyridin-2-ylethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 8.52-8.60 (m, 1H), 7.81 (td, J=1.76, 7.63 Hz,1 H), 7.64-7.71 (m, 2H), 7.26-7.47 (m, 8H), 3.40-3.50 (m, 1H), 3.29-3.37(m, 1H), 3.16-3.26 (m, 0H), 2.83-2.95 (m, J=7.48, 7.48, 14.97 Hz, 1H).

Compound 55N-{5-chloro-2-[(2-pyridin-2-ylethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound (20 mg) was preparedfromN-{5-chloro-2-[(2-pyridin-2-ylethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 8.30 (ddd, J=1.47, 1.61, 4.55 Hz, 1H),7.71-7.76 (m, 2H), 7.61-7.68 (m, 2H), 7.52 (d, J=0.88 Hz, 1H), 7.31-7.36(m, 1H), 7.24-7.31 (m, 2H), 7.18-7.23 (m, 2H), 7.05 (dd, J=2.05, 8.51Hz, 1H), 3.84-3.89 (m, 2H), 3.00-3.14 (m, 2H).

Intermediate 21 2-((2-(1H-pyrazol-4-yl)ethyl)thio)-5-chloroaniline

Following the General Procedure J, the title intermediate was preparedfrom 2-(1H-pyrazol-4-yl)ethanol (472 mg, 4.218 mmol),2-amino-4-chlorobenzenethiol (1.01 g, 6.327 mmol), PPh3 (2.21 g, 8.436mmol) and di-tert-butylazodicarboxylate (1.9 g, 8.436 mmol) in CH₂Cl₂(20 ml).

1H NMR (600 MHz, CD₃OD) δ 7.98 (d, J=0.88 Hz, 1H), 7.64 (s, 1H), 7.23(d, J=8.22 Hz, 1H), 6.76 (d, J=2.35 Hz, 1H), 6.55 (dd, J=2.05, 8.22 Hz,1H), 2.89-3.00 (m, 2H), 2.65-2.77 (m, 2H).

Compound 56N-(5-chloro-2-{[2-(1H-pyrazol-4-yl)ethyl]thio}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure B, the title compound (123 mg) was preparedfrom 2-((2-(1H-pyrazol-4-yl)ethyl)thio)-5-chloroaniline (157 mg, 0.618mmol) and benzofuran-2-sulfonyl chloride (133 mg, 0.618 mmol) inpyridine (3 ml).

1H NMR (600 MHz, CD₃OD) δ 7.70 (d, J=7.92 Hz, 1H), 7.43-7.53 (m, 3H),7.39 (s, 1H), 7.28-7.36 (m, 4H), 7.17 (dd, J=1.76, 8.51 Hz, 1H), 2.82(t, J=7.63 Hz, 2H), 2.45 (t, J=7.63 Hz, 2H).

Compound 57N-(5-chloro-2-{[2-(1H-pyrazol-4-yl)ethyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (52mg, 40%) wasprepared fromN-{5-chloro-2-[(2-pyridin-2-ylethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.75-7.81 (m, 1H), 7.72 (td, J=1.76, 7.63 Hz,1H), 7.67 (d, J=0.88 Hz, 1H), 7.48-7.59 (m, 3H), 7.40-7.45 (m, 2H),7.19-7.34 (m, 3H), 7.17 (d, J=2.35 Hz, 1H), 3.19-3.26 (m, 3H), 2.87 (t,J=7.63 Hz, 2H).

Compound 58N-(5-chloro-2-{[2-(1H-pyrazol-4-yl)ethyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound (75 mg, 73%) wasprepared fromN-{5-chloro-2-[(2-pyridin-2-ylethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.67-7.74 (m, 2H), 7.62 (d, J=7.63 Hz, 1H),7.39 (s, 2H), 7.31 (t, J=7.19 Hz, 2H), 7.22-7.26 (m, 1H), 7.17 (d,J=8.22 Hz, 1H), 6.80-6.90 (m, 1H), 3.89 (br. s., 2H), 2.71-2.81 (m, 2H).

Intermediate 225-Chloro-2-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethylsulfanyl]-phenylamine

Following General Procedure A, the title compound (517 mg, 74%) wasprepared from 2-Amino-4-chloro-benzenethiol (590 mg, 3.693 mmol) and4-(2-bromo-ethyl)-3,5-dimethyl-1H-pyrazole (500mg, 2.462 mmol),K₂CO₃(1.7 g, 12.31 mmol) in DMF (20 ml).

1H NMR (600 MHz, CD₃OD) δ 7.24 (d, J=8.22 Hz, 1H), 6.77 (d, J=2.05 Hz,1H), 6.56 (dd, J=2.35, 8.22 Hz, 1H), 2.75-2.80 (m, 2H), 2.53-2.61 (m,2H), 2.08 (s, 6H).

Compound 59N-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]thio}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure B, the title compound (235 mg) was preparedfrom 2-((2-(1H-pyrazol-4-yl)ethyl)thio)-5-chloroaniline (157 mg, 0.618mmol) and benzofuran-2-sulfonyl chloride (133 mg, 0.618 mmol) inpyridine (3 ml).

1H NMR (600 MHz, CD₃OD) δ 7.68 (dd, J=0.88, 7.92 Hz, 1H), 7.52 (d,J=2.35 Hz, 1H), 7.39-7.47 (m, 3H), 7.27-7.35 (m, 2H), 7.18 (dd, J=2.35,8.51 Hz, 1H), 2.65-2.72 (m, J=7.63 Hz, 2H), 2.28-2.35 (m, 2H), 1.97 (s,6H).

Intermediate 23 5-chloro-2-(((2-fluoropyridin-3-yl)methyl)thio)aniline

(2-Fluoropyridin-3-yl)methanol (508 mg, 3.998 mmol) was first treatedwith SOCl₂ (1.5 ml) in CH₂Cl₂ (5 ml) at rt for 3 hrs. The solvent wasremoved to get a crude 3-(chloromethyl)-2-fluoropyridine. Then followingGeneral Procedure A, the title compound (910 mg, 85%) was prepared from2-amino-4-chlorobenzenethiol (957 mg, 5.995 mmol), K₂CO₃ (2.7 g, 19.98mmol) in DMF (20 ml).

1H NMR (600 MHz, CD₃OD) δ 8.01 (dt, J=0.88, 4.99 Hz, 1H), 7.42 (ddd,J=1.91, 7.48, 9.68 Hz, 1H), 7.10 (ddd, J=1.76, 5.14, 7.19 Hz, 1H), 6.91(d, J=8.22 Hz, 1H), 6.73 (d, J=2.05 Hz, 1H), 6.42 (dd, J=2.35, 8.22 Hz,1H), 3.90 (s, 2H).

Compound 60N-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure B, the title compound (235 mg) was preparedfrom 5-chloro-2-(((2-fluoropyridin-3-yl)methyl)thio)aniline (522 mg,1.948 mmol) and benzofuran-2-sulfonyl chloride (421 mg, 1.948 mmol) inpyridine (5 ml).

1H NMR (600 MHz, acetone-d6) δ 9.00 (br. s., 1H), 8.05 (dt, J=1.47, 4.70Hz, 1H), 7.79 (d, J=6.75 Hz, 1H), 7.55-7.63 (m, 3H), 7.43-7.54 (m, 2H),7.33-7.40 (m, 1H), 7.26 (d, J=8.22 Hz, 1H), 7.07-7.17 (m, 2H), 4.01 (s,2H).

Compound 61N-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (100mg, 59%) wasprepared fromN-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.99 (dd, J=1.91, 4.84 Hz, 1H), 7.65 (d,J=7.34 Hz, 1H), 7.49 (d, J=2.05 Hz, 1H), 7.38 (d, J=8.51 Hz, 1H),7.28-7.33 (m, 1H), 7.19-7.26 (m, 3H), 7.00 (ddd, J=1.47, 5.21, 7.12 Hz,1H), 6.81 (d, J=8.22 Hz, 1H), 6.70 (dd, J=2.05, 8.22 Hz, 1H), 4.43-4.59(m, 2H).

Compound 62N-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound (176mg, 67%) wasprepared fromN-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, acetone-d6) δ 8.04 (d, J=4.70 Hz, 1H), 7.91 (d, J=2.05Hz, 1H), 7.70 (d, J=7.63 Hz, 1H), 7.18-7.44 (m, 6H), 6.90 (t, J=5.43 Hz,1H), 6.67 (d, J=7.63 Hz, 1H), 4.96 (s, 2H).

Intermediate 24 2-(benzylthio)-5-chloroaniline

Following General Procedure A, the title compound (819 mg, 100%) wasprepared from 2-amino-4-chlorobenzenethiol (700 mg, 4.39 mmol),(bromomethyl)benzene (560 mg, 2.92 mmol), K₂CO₃ (2.0 g, 14.62 mmol) inDMF (20 ml).

1H NMR (600 MHz, CD₃OD) δ 7.15-7.24 (m, 3H), 7.07-7.13 (m, 2H), 6.97 (d,J=8.22 Hz, 1H), 6.73 (d, J=2.05 Hz, 1H), 6.43 (dd, J=2.05, 8.22 Hz, 1H),3.86 (s, 2H).

Compound 63 N-[2-(benzylthio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide

Following General Procedure B, the title compound (235 mg) was preparedfrom 2-(benzylthio)-5-chloroaniline(509 mg, 2.052 mmol) andbenzofuran-2-sulfonyl chloride (443 mg, 2.052 mmol) in pyridine (5 ml).

1H NMR (600 MHz, CD₃OD) δ 7.73 (d, J=7.92 Hz, 3H), 7.45-7.56 (m, 3H),7.42 (s, 1H), 7.32-7.38 (m, 1H), 7.10-7.18 (m, 4H), 7.04-7.08 (m, 1H),6.85-6.94 (m, 2H), 3.81 (s, 2H).

Compound 64N-[2-(benzylsulfinyl)-5-chlorophenyl]-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (139mg, 84%) wasprepared fromN-[2-(benzylthio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.65 (d, J=7.92 Hz, 1H), 7.49 (d, J=2.05 Hz,1H), 7.37 (dd, J=0.73, 8.36 Hz, 1H), 7.28-7.33 (m, 1H), 7.16-7.27 (m,3H), 7.08-7.14 (m, 2H), 7.01 (d, J=6.75 Hz, 2H), 6.97 (d, J=8.51 Hz,1H), 6.73 (dd, J=1.91, 8.36 Hz, 1H), 4.50 (d, J=12.91 Hz, 1H), 4.14 (d,J=12.91 Hz, 1H).

Compound 65N-[2-(benzylsulfonyl)-5-chlorophenyl]-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound (212mg, 95%) wasprepared fromN-[2-(benzylthio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.63-7.73 (m, 2H), 7.40 (dd, J=0.73, 8.36 Hz,1H), 7.30-7.37 (m, 3H), 7.23-7.29 (m, 1H), 7.08-7.16 (m, 3H), 6.98-7.05(m, 2H), 6.60 (dd, J=2.05, 8.51 Hz, 1H), 4.99 (s, 2H).

General Procedure K Intermediate 25 2-amino-4-fluorobenzenethiol

A solution of 5-fluoro-2-methylbenzo[d]thiazole (1.2 g, 7.18 mmol) inethylene glycol and NaOH (5N, 2 ml) was degassed under N₂ for 10 min,then refluxed at 129° C. for 3 hours. The solution was cooled to 0° C.and then acidified to pH 3˜4 using c. HCl. The mixture was extractedwith EtOAc (2×50 ml). The organic layer was washed with brine and driedwith Na₂SO₄ and concentrated in vacuo. The crude residue (1.01 g, 98%)was used directly in the next step without purification.

1H NMR (600 MHz, CD₃OD) δ 7.24 (dd, J=6.16, 8.51 Hz, 1H), 6.97 (dd,J=6.46, 8.51 Hz, 1H), 6.20 (td, J=2.79, 8.58 Hz, 1H).

Intermediate 26 5-fluoro-2-((3-nitrobenzyl)thio)aniline

Following General Procedure A, the title compound (460 mg, 97%) wasprepared from 2-amino-4-fluorobenzenethiol (562 g, 3.93 mmol),1-(bromomethyl)-3-nitrobenzene (566 mg, 2.62 mmol), K₂CO₃ (1.8 g, 13.10mmol) in DMF (10 ml).

1H NMR (600 MHz, CD₃OD) δ 8.04 (dt, J=2.09, 7.26 Hz, 1H), 7.89 (s, 1H),7.34-7.54 (m, 2H), 6.93 (dd, J=6.46, 8.51 Hz, 1H), 6.35-6.53 (m, 1H),6.15 (td, J=2.64, 8.51 Hz, 1H), 3.95 (s, 2H).

Compound 66N-(5-fluoro-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide

Following General Procedure B, the title compound (474 mg, 63%) wasprepared from 2-((3-aminobenzyl)thio)-5-fluoroaniline (460 mg, 1.655mmol) and benzofuran-2-sulfonyl chloride (357 mg, 1.655 mmol) inpyridine (5 ml).

1H NMR (600 MHz, CD₃OD) δ 7.98 (ddd, J=0.88, 2.35, 8.22 Hz, 1H),7.68-7.79 (m, 2H), 7.49-7.54 (m, 2H), 7.42-7.48 (m, 1H), 7.25-7.39 (m,4H), 7.16 (dd, J=6.16, 8.80 Hz, 1H), 6.78 (td, J=2.93, 8.36 Hz, 1H),3.91 (s, 2H).

General Procedure L Compound 67N-{2-[(3-aminobenzyl)thio]-5-fluorophenyl}-1-benzofuran-2-sulfonamide

N-(5-fluoro-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide (91mg, 0.199 mmol) was dissolved in MeOH (2 ml). Zn (322 mg, 4.967 mmol)and NH₄Cl (1 ml) was added to the solution. After the mixture wasstirred for 30 min at room temperature, the solid was filtered and thefiltrate was concentrated in vacuo and then the crude residue waspurified by column chromatography (0˜30% EtOAc in hexane) to afford thetitle product (50 mg, 59%).

1H NMR (600 MHz, CD₃OD) δ 7.71 (d, J=7.92 Hz, 1H), 7.50-7.54 (m, 1H),7.48 (d, J=0.88 Hz, 1H), 7.46 (ddd, J=1.32, 7.26, 8.44 Hz, 1H),7.28-7.38 (m, 2H), 7.19 (dd, J=6.16, 8.80 Hz, 1H), 6.83-6.89 (m, 1H),6.77 (td, J=2.79, 8.44 Hz, 1 H), 6.46-6.54 (m, 1H), 6.36 (t, J=1.76 Hz,1H), 6.22 (d, J=7.63 Hz, 1H), 3.63 (s, 2H).

Compound 68N-{2-[(3-aminobenzyl)sulfinyl]-5-fluorophenyl}-1-benzofuran-2-sulfonamide

Following General Procedure L, the title compound (130mg, 84%) wasprepared fromN-{5-fluoro-2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.75 (dd, J=0.88, 7.92 Hz, 1H), 7.53-7.60 (m,2H), 7.48 (ddd, J=1.32, 7.26, 8.44 Hz, 1H), 7.33-7.38 (m, 1H), 7.28 (dd,J=6.16, 8.80 Hz, 1H), 7.14 (dd, J=2.64, 10.27 Hz, 1H), 6.88-7.02 (m,2H), 6.71 (dt, J=1.06, 8.14 Hz, 1H), 6.57 (s, 1H), 6.41 (d, J=7.63 Hz,1H), 4.24 (d, J=12.62 Hz, 1H), 4.06 (d, J=12.91 Hz, 1H).

Compound 69N-{5-fluoro-2-[(3-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound (136 mg, 74%) wasprepared fromN-(5-fluoro-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 8.10 (ddd, J=1.17, 2.13, 8.14 Hz, 1H),7.72-7.81 (m, 3H), 7.65 (dd, J=6.02, 8.95 Hz, 1H), 7.55 (d, J=8.51 Hz,1H), 7.45-7.51 (m, 3H), 7.41-7.45 (m, 1H), 7.33-7.39 (m, 1H), 6.80-7.09(m, 1H), 4.70 (s, 2H).

Compound 70N-{2-[(3-aminobenzyl)sulfonyl]-5-fluorophenyl}-1-benzofuran-2-sulfonamide

Following General Procedure L, the title compound (91mg, 81%) wasprepared fromN-{5-fluoro-2-[(3-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, acetone-d6) δ 7.87 (br. s., 1H), 7.84 (d, J=7.92 Hz,2H), 7.57-7.65 (m, 2H), 7.50-7.56 (m, 2H), 7.39 (t, J=7.48 Hz, 1H),6.94-7.02 (m, 1H), 6.83 (t, J=7.78 Hz, 1H), 6.53 (d, J=8.80 Hz, 1H),6.38 (s, 1H), 6.13 (d, J=7.34 Hz, 1H), 4.38 (s, 2H).

Intermediate 27 5-methoxy-2-((3-nitrobenzyl)thio)aniline

Following General Procedure K and A, the title compound (474 mg) wasprepared from 5-methoxy-2-methylbenzo[d]thiazole.

1H NMR (600 MHz, CD₃OD) δ 8.03 (dt, J=2.05, 7.34 Hz, 1H), 7.84 (d,J=1.76 Hz, 1H), 7.34-7.48 (m, 2H), 6.83 (d, J=8.51 Hz, 1H), 6.32 (s,1H), 6.06 (dd, J=2.79, 8.36 Hz, 1H), 3.90 (s, 2H), 3.69 (s, 3H).

Compound 71N-{2-[(3-aminobenzyl)thio]-5-methoxyphenyl}-1-benzofuran-2-sulfonamide

Following General Procedure L, the title compound (82mg, 70%) wasprepared fromN-(5-methoxy-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.69 (d, J=7.92 Hz, 1H), 7.50 (dd, J=0.88,8.51 Hz, 1H), 7.40-7.47 (m, 2H), 7.31 (ddd, J=1.03, 7.19, 7.92 Hz, 1H),7.07-7.13 (m, 2H), 6.84-6.90 (m, 1H), 6.57 (dd, J=2.79, 8.66 Hz, 1H),6.50-6.54 (m, 1H), 6.37 (t, J=1.91 Hz, 1H), 6.25 (d, J=7.63 Hz, 1H),3.72 (s, 3H), 3.57 (s, 2H).

Compound 72N-{5-methoxy-2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (95mg, 46%) wasprepared fromN-(5-methoxy-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.

1H NMR (600 MHz, acetone-d6) δ 10.74 (br. s., 1H), 8.16 (ddd, J=0.88,2.35, 8.22 Hz, 1H), 7.78-7.86 (m, 2H), 7.75 (s, 1H), 7.61 (dd, J=0.88,8.51 Hz, 1H), 7.56 (t, J=7.92 Hz, 1H), 7.44-7.52 (m, 2H), 7.35-7.40 (m,1H), 7.09 (d, J=2.35 Hz, 1H), 7.06 (d, J=8.80 Hz, 1H), 6.69 (dd, J=2.49,8.66 Hz, 1H), 4.45-4.53 (m, 2H), 3.77 (s, 3H).

Compound 73N-{2-[(3-aminobenzyl)sulfinyl]-5-methoxyphenyl}-1-benzofuran-2-sulfonamide

Following General Procedure L, the title compound (55mg, 65%) wasprepared fromN-{5-methoxy-2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, acetone-d6) δ 7.75-7.85 (m, 2H), 7.59 (dd, J=0.59, 8.51Hz, 1H), 7.44-7.53 (m, 1H), 7.32-7.40 (m, 1H), 7.25 (s, 1H), 6.93 (d,J=8.51 Hz, 1H), 6.85-6.90 (m, 1H), 6.61 (dd, J=2.49, 8.66 Hz, 1H),6.53-6.58 (m, 1H), 6.40 (t, J=1.76 Hz, 1H), 6.21 (d, J=7.92 Hz, 1H),4.25 (d, J=12.32 Hz, 1H), 4.08 (d, J=11.74 Hz, 2H), 3.78 (s, 3H).

Compound 74N-(5-methoxy-2-((3-nitrobenzyl)sulfonyl)phenyl)benzofuran-2-sulfonamide

Following General Procedure D, the title compound (165mg, 83%) wasprepared fromN-(5-methoxy-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.

1H NMR (600 MHz, CDCl₃) δ 9.28 (s, 1H), 8.14-8.19 (m, 1H), 7.70 (d,J=7.63 Hz, 1H), 7.64 (s, 1H), 7.58 (s, 1H), 7.41-7.50 (m, 3H), 7.37 (d,J=9.10 Hz, 1H), 7.33 (td, J=1.03, 7.41 Hz, 1H), 7.29 (d, J=2.35 Hz, 1H),7.26 (s, 1H), 6.57 (dd, J=2.35, 8.80 Hz, 1H), 4.38 (s, 2H), 3.86 (s,3H).

Compound 75N-{2-[(3-aminobenzyl)sulfonyl]-5-methoxyphenyl}-1-benzofuran-2-sulfonamide

Following General Procedure L, the title compound (67mg, 45%) wasprepared fromN-(5-methoxy-2-((3-nitrobenzyl)sulfonyl)phenyl)benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.70 (d, J=7.63 Hz, 1H), 7.42-7.50 (m, 2H),7.35-7.41 (m, 1H), 7.33 (d, J=8.80 Hz, 1H), 7.27-7.31 (m, 1H), 7.22 (d,J=2.35 Hz, 1H), 6.76 (t, J=7.78 Hz, 1H), 6.53 (dd, J=1.32, 8.07 Hz, 1H),6.45 (s, 1H), 6.39 (d, J=8.51 Hz, 1H), 6.27 (d, J=7.63 Hz, 1H), 4.61(br. s., 2H), 3.76 (s, 3H).

Compound 76 Benzofuran-2-sulfonic acid[2-(3-nitro-benzylsulfanyl)-phenyl]-amide

Following General Procedure B, the title compound (520 mg, 41%) wasprepared from 2-((3-nitrobenzyl)thio)aniline (741 mg, 2.85 mmol),benzofuran-2-sulfonyl chloride (616 mg, 2.85 mmol) in pyridine (10 ml).

1H NMR (600 MHz, CD₃OD) δ 7.97-8.04 (m, 1H), 7.79-7.89 (m, 1H), 7.70 (d,J=0.88 Hz, 1H), 7.50 (d, J=0.88 Hz, 1H), 7.29-7.47 (m, 6H), 7.15-7.25(m, 2H), 7.02-7.11 (m, 1H), 3.99 (s, 2H).

Compound 77 N-{2-[(3-aminobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure L, the title compound (67mg, 45%) wasprepared from benzofuran-2-sulfonic acid[2-(3-nitro-benzylsulfanyl)-phenyl]-amide.

1H NMR (600 MHz, CD₃OD) δ 7.66 (d, J=7.92 Hz, 1H), 7.47-7.52 (m, 1H),7.38-7.46 (m, 2H), 7.26-7.35 (m, 2H), 7.12-7.22 (m, 2H), 7.04 (td,J=1.47, 7.63 Hz, 1H), 6.88 (t, J=7.78 Hz, 1H), 6.54 (dd, J=1.47, 7.92Hz, 1H), 6.43 (t, J=1.76 Hz, 1H), 6.28 (d, J=7.63 Hz, 1H), 3.69 (s, 2H).

Compound 78N-{2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (172mg, 73%) wasprepared from benzofuran-2-sulfonicacid[2-(3-nitro-benzylsulfanyl)-phenyl]-amide.

1H NMR (600 MHz, acetone-d6) δ 10.45 (br. s., 1H), 8.15 (d, J=8.22 Hz,1H), 7.85 (s, 1H), 7.80 (d, J=7.92 Hz, 1H), 7.66 (d, J=0.88 Hz, 1H),7.59-7.63 (m, 1H), 7.42-7.57 (m, 5H), 7.34-7.40 (m, 1H), 7.13-7.24 (m,2H), 4.54-4.60 (m, 1H), 4.45-4.51 (m, 1H).

Compound 79N-{2-[(3-aminobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure L, the title compound (122 mg, 90%) wasprepared fromN-{2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.73 (d, J=7.63 Hz, 1H), 7.59 (d, J=8.22 Hz, 1H), 7.43-7.53 (m, 3H), 7.29-7.42 (m, 3H), 7.20 (d, J=7.63 Hz, 1H), 6.97(t, J=7.63 Hz, 1H), 6.66 (d, J=7.34 Hz, 1H), 6.57 (br. s., 1H), 6.43 (d,J=7.34 Hz, 1H), 4.27 (d, J=12.91 Hz, 1H), 3.99 (d, J=12.91 Hz, 1H).

Compound 80N-{2-[(3-aminobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure L, the title compound (75 mg, 82%) wasprepared fromN-{2-[(3-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, acetone-d6)) δ 7.75-7.85 (m, 3H), 7.62-7.70 (m, 1H),7.59 (d, J=8.51 Hz, 1H), 7.56 (dd, J=1.76, 7.92 Hz, 1H), 7.49 (td,J=1.17, 7.92 Hz, 1H), 7.36 (t, J=7.48 Hz, 1H), 7.16-7.22 (m, 1H), 6.83(t, J=7.78 Hz, 1H), 6.57 (dd, J=1.47, 7.92 Hz, 1H), 6.43 (t, J=1.91 Hz,1H), 6.15 (d, J=7.34 Hz, 1H), 4.37 (s, 2H).

Intermediate 28 5-chloro-2-((4-nitrobenzyl)thio)aniline

Following General Procedure A, the title compound (624 mg, 92%) wasprepared from 2-amino-4-chlorobenzenethiol (555 mg, 3.10 mmol),1-(bromomethyl)-4-nitrobenzene (490 mg, 2.268 mmol) and K₂CO₃ (1.3 g,9.50 mmol) in DMF (20 ml).

1H NMR (600 MHz, CD₃OD) δ 8.07 (d, J=8.80 Hz, 2H), 7.30 (d, J=8.80 Hz,2H), 6.93 (d, J=8.22 Hz, 1H), 6.73 (d, J=2.35 Hz, 1H), 6.43 (dd, J=2.35,8.22 Hz, 1H), 3.97 (s, 2H).

Compound 81N-{5-chloro-2-[(4-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure B, the title compound (475 mg, 72%) wasprepared from 5-chloro-2-((4-nitrobenzyl)thio)aniline (411 mg, 1.40mmol) and benzofuran-2-sulfonyl chloride (303 mg, 1.40 mmol) in pyridine(5 ml).

1H NMR (600 MHz, CD₃OD) δ 7.94-8.00 (m, 2H), 7.72 (d, J=7.92 Hz, 1H),7.50-7.55 (m, 1H), 7.45-7.49 (m, 2H), 7.43 (s, 1H), 7.31-7.38 (m, 1H),7.11-7.19 (m, 3H), 7.07 (dd, J=2.35, 8.51 Hz, 1H), 3.96 (s, 2H).

Compound 82N-{5-chloro-2-[(4-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound (120mg, 85%) wasprepared fromN-{5-chloro-2-[(4-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, acetone-d6) δ 9.59 (br. s., 1H), 8.01 (d, J=7.34 Hz,2H), 7.86 (s, 1H), 7.76 (d, J=7.92 Hz, 1H), 7.72 (s, 1H), 7.52 (d,J=8.51 Hz, 1H), 7.39-7.49 (m, 2H), 7.25-7.36 (m, 3H), 7.00 (s, 1H), 4.96(s, 2H).

Compound 83N-{2-[(4-aminobenzyl)sulfonyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide

Following General Procedure L, the title compound (68 mg, 81%) wasprepared fromN-{5-chloro-2-[(4-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, acetone-d6) δ 7.75-7.88 (m, 3H), 7.61 (d, J=8.51 Hz, 1H), 7.44-7.54 (m, 2H), 7.34-7.41 (m, 1H), 7.22 (dd, J=1.76, 8.51 Hz,1H), 6.69 (d, J=8.51 Hz, 2H), 6.49 (d, J=8.51 Hz, 2H), 4.38 (s, 2H).

Intermediate 29 5-chloro-2-((2-nitrobenzyl)thio)aniline

Following General Procedure A, the title compound (548 mg, 95%) wasprepared from 2-amino-4-chlorobenzenethiol (441 mg, 2.76 mmol),1-(bromomethyl)-2-nitrobenzene (398 mg, 1.84 mmol) and K₂CO₃ (1.27 g,9.21 mmol) in DMF (20 ml).

1H NMR (600 MHz, CD₃OD) δ 7.89-7.98 (m, 1H), 7.37-7.46 (m, 2H),6.99-7.04 (m, 1H), 6.81 (d, J=8.22 Hz, 1H), 6.71 (d, J=2.05 Hz, 1H),6.37 (dd, J=2.05, 8.22 Hz, 1H), 4.22 (s, 2H).

Compound 84N-(5-chloro-2-((2-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide

Following General Procedure B, the title compound (485 mg, 69%) wasprepared from 5-chloro-2-((2-nitrobenzyl)thio)aniline (435 mg, 1.48mmol) and benzofuran-2-sulfonyl chloride (320 mg, 1.48 mmol) in pyridine(5 ml).

1H NMR (600 MHz, CDCl₃) δ 8.03 (dd, J=1.47, 7.92 Hz, 1H), 7.65-7.71 (m,2H), 7.48-7.53 (m, 2H), 7.43-7.48 (m, 1H), 7.31-7.42 (m, 3H), 7.03 (d,J=8.22 Hz, 1H), 6.90 (dd, J=2.05, 8.22 Hz, 1H), 6.76 (dd, J=1.32, 7.48Hz, 1H), 4.16 (s, 2H).

Compound 85

N-{2-[(2-aminobenzyl)thio]-5-chlorophenyl}-1-benzofuran-2-sulfonamide

Following General Procedure L, the title compound (44 mg, 40%) wasprepared fromN-(5-chloro-2-((2-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.

1H NMR (600 MHz, acetone-d6) δ 7.77 (d, J=7.92 Hz, 1H), 7.59 (dd,J=0.88, 8.51 Hz, 1H), 7.47-7.55 (m, 3H), 7.31-7.41 (m, 2H), 7.10 (dd,J=2.35, 8.51 Hz, 1H), 6.86-6.95 (m, 1H), 6.72 (dd, J=0.88, 7.92 Hz, 1H),6.57 (dd, J=1.32, 7.48 Hz, 1H), 6.38 (td, J=1.03, 7.41 Hz, 1H), 3.97 (s,2H).

Compound 86N-{5-chloro-2-[(2-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (160mg, 79%) wasprepared fromN-(5-chloro-2-((2-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.

1H NMR (600 MHz, acetone-d6) δ 7.92 (d, J=8.22 Hz, 1H), 7.71 (dd,J=0.73, 7.78 Hz, 1H), 7.59 (d, J=2.05 Hz, 1H), 7.47 (d, J=8.51 Hz, 1H),7.39-7.44 (m, 1H), 7.33-7.38 (m, 2H), 7.19-7.30 (m, 2H), 6.71-6.80 (m,2H), 6.67 (d, J=8.22 Hz, 1H), 5.13 (d, J=12.91 Hz, 2H), 4.73 (d, J=12.62Hz, 2H).

Compound 87N-{2-[(2-aminobenzyl)sulfinyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide

Following General Procedure L, the title compound (67 mg, 50%) wasprepared fromN-{5-chloro-2-[(2-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.72 (d, J=7.92 Hz, 1H), 7.56 (d, J=7.63 Hz,1H), 7.44-7.52 (m, 2H), 7.41 (d, J=8.51 Hz, 2H), 7.31-7.37 (m, 1H), 7.28(d, J=1.47 Hz, 1H), 7.21 (dd, J=1.76, 8.22 Hz, 1H), 7.06-7.13 (m, 1H),6.88 (d, J=7.92 Hz, 1H), 6.75 (d, J=7.04 Hz, 1H), 6.60-6.67 (m, 1H),4.50 (d, J=13.50 Hz, 2H), 4.23 (d, J=12.91 Hz, 2H).

Compound 88N-{2-[(2-aminobenzyl)sulfonyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D and K, the title compound (52 mg) wasprepared fromN-(5-chloro-2-((2-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.

1H NMR (300 MHz, CD₃OD) δ 7.69-7.78 (m, 2H), 7.56-7.65 (m, 2H),7.50-7.55 (m, 1H), 7.45 (td, J=1.17, 7.77 Hz, 1H), 7.28-7.38 (m, 1H),6.99-7.15 (m, 2H), 6.88 (d, J=7.03 Hz, 1H), 6.67-6.75 (m, 1H), 6.58-6.66(m, 1H), 4.68 (s, 2H).

Intermediate 30 5-chloro-2-((pyrimidin-2-ylmethyl)thio)aniline

Following General Procedure A, the title compound (284 mg, 39%) wasprepared from 2-amino-4-chlorobenzenethiol (529 mg, 3.33 mmol),2-(chloromethyl)pyrimidine (366 mg, 2.22 mmol) and K₂CO₃ (1.53 g, 11.09mmol) in DMF (10 ml).

1H NMR (600 MHz, CD₃OD) δ 8.65 (d, J=4.99 Hz, 2H), 7.31 (t, J=4.99 Hz, 1H), 7.03 (d, J=8.22 Hz, 1H), 6.70 (s, 1H), 6.43 (dd, J=2.05, 8.22 Hz,1H), 4.07 (s, 2H).

Compound 89N-{5-chloro-2-[(pyrimidin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure B, the title compound (243 mg, 51%) wasprepared from 5-chloro-2-((pyrimidin-2-ylmethyl)thio)aniline (280 mg,1.11 mmol) and benzofuran-2-sulfonyl chloride (240 mg, 1.11 mmol) inpyridine (3 ml).

1H NMR (600 MHz, acetone-d6) δ 11.69 (br. s., 1H), 8.87 (d, J=4.99 Hz,2H), 7.74 (dd, J=0.88, 7.92 Hz, 1H), 7.66 (s, 1H), 7.62 (d, J=8.22 Hz,1H), 7.59 (d, J=0.59 Hz, 1H), 7.45-7.52 (m, 3H), 7.33 (ddd, J=1.76,6.38, 8.00 Hz, 1H), 7.14 (dd, J=2.20, 8.36 Hz, 1H), 4.24 (s, 2H).

Compound 90N-{5-chloro-2-[(pyrimidin-2-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (82mg) was preparedfromN-{5-chloro-2-[(pyrimidin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 8.68 (dd, J=1.47, 4.99 Hz, 2H), 7.73 (d,J=7.92 Hz, 1H), 7.53-7.60 (m, 2H), 7.45-7.52 (m, 2H), 7.30-7.41 (m, 4H),4.63 (d, J=13.50 Hz, 1H), 4.46 (d, J=13.50 Hz, 1H).

Compound 91N-{5-chloro-2-[(pyrimidin-2-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound (60 mg) was preparedfromN-{5-chloro-2-[(pyrimidin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, DMSO-d6) δ 8.68 (dd, J=1.47, 4.99 Hz, 2H), 7.76 (s,1H), 7.68 (br. s., 1H), 7.61 (d, J=8.22 Hz, 1H), 7.54-7.58 (m, 2H), 7.46(t, J=7.34 Hz, 1H), 7.41 (t, J=4.84 Hz, 1H), 7.30-7.37 (m, 1H), 7.19 (d,J=7.92 Hz, 1H), 5.11-5.19 (m, 2H).

General Procedure M Intermediate 31 4-mercapto-3-nitrobenzonitrile

To a solution of 4-chloro-3-nitrobenzonitrile (530 mg, 2.88 mmol) indioxane (5 ml)/water (1 ml) was added Na₂S.9H₂O 9692 mg, 2.88 mmol).After it was stirred at room temperature for 2 hours, the reaction wasquenched with HCl (1N). The mixture was extracted with EtOAc (2×50 ml).The organic layer was washed with water, brine, dried over Na₂SO₄ andconcentrated in vacuo. The title compound was purified by silica gelcolumn chromatography (0˜30% EtOAc in hexane).

1H NMR (600 MHz, acetone-d6) δ 8.67 (d, J=1.76 Hz, 1H), 8.01 (s, 1H),7.93 (dd, J=1.76, 8.51 Hz, 1H), 5.30 (s, 1H).

Intermediate 32 4-(benzylthio)-3-nitrobenzonitrile

Following General Procedure A, the title compound (580 mg, 82%) wasprepared from 4-mercapto-3-nitrobenzonitrile (473 mg, 2.63 mmol),(bromomethyl)benzene (449 mg, 2.63 mmol), K₂CO₃ (1.81 g, 13.14 mmol) inDMF (10 ml).

1H NMR (600 MHz, DMSO-d₆) δ 8.68 (d, J=1.76 Hz, 1H), 8.10 (dd, J=1.47,8.51 Hz, 1H), 7.88 (d, J=8.51 Hz, 1H), 7.43 (d, J=7.34 Hz, 2H), 7.34 (t,J=7.63 Hz, 2H), 7.25-7.30 (m, 1H), 4.44 (s, 2H).

Intermediate 33 3-amino-4-(benzylthio)benzonitrile

Following General Procedure L, the title compound (372 mg, 81%) wasprepared from 4-(benzylthio)-3-nitrobenzonitrile (518 mg, 1.92 mmol).

1H NMR (600 MHz, CD₃OD) δ 7.11-7.25 (m, 6H), 6.96 (d, J=1.76 Hz, 1H),6.71-6.78 (m, 1H), 4.00 (s, 2H).

Compound 92 N[2-(benzylthio)-5-cyanophenyl]-1-benzofuran-2-sulfonamide

Following General Procedure B, the title compound (419 mg, 65%) wasprepared from 3-amino-4-(benzylthio)benzonitrile (370 mg, 1.54 mmol) andbenzofuran-2-sulfonyl chloride (333 mg, 1.54 mmol) in pyridine (3 ml).

1H NMR (600 MHz, CD₃OD) δ 7.73 (d, J=8.51 Hz, 1H), 7.65 (d, J=1.17 Hz, 1H), 7.50-7.56 (m, 2H), 7.48 (dd, J=1.47, 8.22 Hz, 1H), 7.39 (ddd,J=2.05, 6.16, 7.92 Hz, 1H), 7.31-7.36 (m, 2H), 7.09-7.20 (m, 3H), 6.92(d, J=7.04 Hz, 2H), 3.97 (s, 2H).

Compound 93N-[2-(benzylsulfinyl)-5-cyanophenyl]-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (109 mg) was preparedfrom N-[2-(benzylthio)-5-cyanophenyl]-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.74 (d, J=7.63 Hz, 1H), 7.66 (s, 1H), 7.53(d, J=8.51 Hz, 1H), 7.50 (s, 1H), 7.45 (t, J=7.48 Hz, 1H), 7.30-7.39 (m,2H), 7.28 (d, J=7.92 Hz, 1H), 7.20-7.25 (m, 1H), 7.16 (t, J=7.48 Hz,2H), 6.96 (d, J=7.34 Hz, 2H), 4.47 (d, J=13.21 Hz, 1H), 4.21 (d, J=12.91Hz, 1H).

Compound 94N-[2-(benzylsulfonyl)-5-cyanophenyl]-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound (230 mg) was preparedfrom N-[2-(benzylthio)-5-cyanophenyl]-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.97 (d, J=1.47 Hz, 1H), 7.68 (d, J=7.63 Hz,1H), 7.52 (d, J=8.22 Hz, 1H), 7.43 (s, 1H), 7.32-7.38 (m, 2H), 7.24-7.30(m, 1H), 7.09-7.18 (m, 3H), 6.98-7.06 (m, 2H), 6.87 (dd, J=1.47, 8.22Hz, 1H), 5.05 (s, 2H).

Compound 954-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure B and D, the title compound was preparedfrom 5-chloro-2-(methylthio)aniline and4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.

1H NMR (300 MHz, CD₃OD) δ 8.26 (s, 1H), 8.11 (d, J=8.50 Hz, 1H),7.74-7.87 (m, 2H), 7.58 (d, J=1.47 Hz, 1H), 7.16 (d, J=8.50 Hz, 1H),3.19 (s, 3H).

Compound 964-chloro-N-[5-chloro-2-(methylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure B, the title compound was prepared from5-chloro-2-(methylthio)aniline and4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.

1H NMR (300 MHz, CDCl3) δ 8.13 (d, J=1.47 Hz, 1H), 7.88 (dd, J=1.90,8.35 Hz, 1H), 7.60 (dd, J=2.64, 12.60 Hz, 2H), 7.28 (d, J=8.50 Hz, 1H),7.10 (dd, J=2.05, 8.50 Hz, 1H), 2.21 (s, 3H).

Compound 974-chloro-N-[5-chloro-2-(isopropylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure A and B, the title compound was preparedfrom 2-amino-4-chloro-benzenethiol, 2-iodo-propane, and4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.

1H NMR (300 MHz, CD₃OD) δ 8.13 (d, J=1.47 Hz, 1H), 7.92 (dd, J=2.05,8.50 Hz, 1H), 7.76 (d, J=8.50 Hz, 1H), 7.53 (d, J=2.05 Hz, 1H), 7.33 (d,J=8.50 Hz, 1H), 7.15-7.23 (m, 1H), 3.03-3.21 (m, 1H), 1.06 (d, J=6.45Hz, 6H).

Compound 984-chloro-N-{5-chloro-2-[(2-hydroxyethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure A and B, the title compound was preparedfrom 2-amino-4-chloro-benzenethiol, 2-bromo-ethanol, and4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.

1H NMR (300 MHz, CD₃OD) δ 8.09 (d, J=1.47 Hz, 1H), 7.92 (dd, J=1.90,8.35 Hz, 1H), 7.76 (d, J=8.50 Hz, 1H), 7.51 (d, J=2.34 Hz, 1H), 7.41 (d,J=8.50 Hz, 1H), 7.20 (dd, J=2.20, 8.35 Hz, 1H), 3.49 (t, J=6.15 Hz, 2H),2.80 (t, J=6.15 Hz, 2H).

Compound 994-chloro-N-[5-chloro-2-(isopropylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure C, the title compound (55 mg) was preparedfrom4-chloro-N-[5-chloro-2-(isopropylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide.

Compound 1004-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure C, the title compound (109 mg) was preparedfrom4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide.

1H NMR (300 MHz, CD₃OD) δ 8.09 (d, J=1.17 Hz, 1H), 7.96-8.03 (m, 1H),7.84 (d, J=8.20 Hz, 1H), 7.71 (d, J=8.50 Hz, 1H), 7.44 (dd, J=1.76, 8.50Hz, 1H), 7.21 (d, J=1.76 Hz, 1H), 3.98 (td, J=4.10, 8.06 Hz, 1H),3.77-3.88 (m, 1H), 3.19 (ddd, J=5.27, 8.42, 13.26 Hz, 1H), 2.95-3.06 (m,1H).

Compound 1014-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure D, the title compound was prepared from4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide.

1H NMR (600 MHz, CD₃OD) δ 8.27 (d, J=1.47 Hz, 1H), 8.11 (dd, J=2.05,8.51 Hz, 1H), 7.74 (dd, J=8.51, 14.97 Hz, 2H), 7.54-7.59 (m, 1H),6.96-7.08 (m, 1H), 3.82 (t, J=6.02 Hz, 2H), 3.57-3.68 (m, 2H).

Compound 102 methyl3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propanoate

Following General Procedure H, B, and C, the title compound was preparedfrom 2-amino-4-chlorobenzenethiol.

1H NMR (300 MHz, CD₃OD) δ 8.09 (s, 1H), 7.99 (dd, J=1.76, 8.50 Hz, 1H),7.85 (d, J=8.20 Hz, 1H), 7.71 (d, J=8.50 Hz, 1H), 7.47 (dd, J=1.61, 8.35Hz, 1H), 7.11 (d, J=1.76 Hz, 1H), 3.63 (s, 3H), 3.24-3.39 (m, 1H),3.08-3.22 (m, 1H), 2.54-2.82 (m, 2H).

Compound 1034-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure A and B, the title compound was preparedfrom 2-amino-4-chlorobenzenethiol.

1H NMR (600 MHz, CD₃OD) δ 8.63 (d, J=3.81 Hz, 1H), 8.03 (d, J=2.35 Hz, 1H), 7.87 (dd, J=2.20, 8.36 Hz, 1H), 7.75 (td, J=1.76, 7.63 Hz, 1H), 7.70(d, J=8.51 Hz, 1H), 7.54 (d, J=2.35 Hz, 1H), 7.37 (d, J=8.51 Hz, 1H),7.32-7.35 (m, 1 H), 7.21 (d, J=7.63 Hz, 1H), 7.13 (dd, J=2.35, 8.22 Hz,1H), 4.00 (s, 2H).

Compound 1044-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure A and B, the title compound was preparedfrom 2-amino-4-chlorobenzenethiol.

1H NMR (600 MHz, CD₃OD) δ 8.38 (d, J=3.82 Hz, 1H), 8.25 (br. s., 1H),8.11 (d, J=2.35 Hz, 1H), 7.93 (dd, J=2.05, 8.51 Hz, 1H), 7.78 (d, J=8.51Hz, 1H), 7.60 (dt, J=1.91, 7.92 Hz, 1H), 7.39 (d, J=2.35 Hz, 1H), 7.33(dd, J=4.84, 7.78 Hz, 1H), 7.20 (d, J=8.51 Hz, 1H), 7.14 (s, J=2.35,2.35, 8.51, 8.51 Hz, 1H), 3.95 (s, 2H).

Compound 1054-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure C, the title compound was prepared from4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide.

1H NMR (600 MHz, DMSO-d6) d 8.44 (d, J=4.40 Hz, 1H), 8.03 (d, J=2.05 Hz,1H), 7.98 (dd, J=2.05, 8.22 Hz, 1H), 7.88 (d, J=8.22 Hz, 1H), 7.74 (t,1H), 7.25-7.33 (m, 2H), 7.20 (d, J=7.63 Hz, 1H), 7.14 (br. s., 1H), 7.03(d, J=1.47 Hz, 1H), 4.49 (d, J=12.62 Hz, 1H), 4.06 (d, J=12.91 Hz, 1H).

Compound 1064-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure C, the title compound was prepared from4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide.

1H NMR (600 MHz, CD₃OD) d 8.35 (dd, J=1.61, 4.84 Hz, 1H), 8.24 (d,J=2.35 Hz, 1H), 8.07 (d, J=2.05 Hz, 1H), 8.03 (d, J=1.76 Hz, 1H), 7.71(d, J=8.51 Hz, 1H), 7.38 (s, 1H), 7.27 (d, J=2.05 Hz, 1H), 7.23-7.26 (m,1H), 6.75 (d, J=8.22 Hz, 1H), 6.65 (dd, J=1.91, 8.36 Hz, 1H), 4.45 (d,J=13.50 Hz, 1H), 4.37 (d, J=13.21 Hz, 1H).

General Procedure N Intermediate 344-Chloro-N-(5-chloro-2-mercapto-phenyl)-3-trifluoromethyl-benzenesulfonamide

To a solution ofN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide]Intermediate 5 (106 mg, 0.13 mmol) in THF (3 ml) at 0° C. was addedNaBH₄ (20 mg, 0.53 mmol), the mixture was stirred at room temperaturefor 1 h, diluted with H₂O, acidified carefully with 6 M HCl, extractedwith EtOAc. The organic layer was washed with brine, dried over Na₂SO₄,and concentrated in vacuo to yield 109 mg off-white solid as the titlecompound.

¹H NMR (600 MHz, METHANOL-d₄) δ 8.05 (s, 1H), 7.91 (d, J=8.51 Hz, 1H),7.78 (d, J=8.51 Hz, 1H), 7.30 (dd, J=1.47, 8.22 Hz, 1H), 7.23-7.25 (m,1H), 7.14 (dd, J=2.20, 8.36 Hz, 1H).

Compound 107ethyl{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}acetate

Following General Procedure A and C, the title compound was preparedfrom4-Chloro-N-(5-chloro-2-mercapto-phenyl)-3-trifluoromethyl-benzenesulfonamideIntermediate 34 and ethyl 2-bromoacetate.

1H NMR (300 MHz, CD₃OD) d 8.06 (s, 1H), 7.96 (d, J=8.50 Hz, 1H), 7.84(dd, J=8.50, 10.84 Hz, 2H), 7.52 (dd, J=1.61, 8.64 Hz, 1H), 7.06 (d,J=1.47 Hz, 1H), 4.17 (q, J=7.23 Hz, 2H), 4.06 (d, J=14.65 Hz, 1H), 3.88(d, J=14.36 Hz, 1H), 1.22 (t, J=7.18 Hz, 3H).

General Procedure O Intermediate 354-Chloro-N-[5-chloro-2-(3-oxo-cyclopentylsulfanyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide

To a solution ofN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide]Intermediate 5 (105 mg, 0.13 mmol) in CH₂Cl₂ (2 ml), MeOH (0.5 ml), andH₂O (0.25 ml) was added polymer-bound triphenylphosphine (˜3 mmol/gtriphenylphosphine loading, 87 mg, 0.26 mmol), cyclopent-2-enone (33 μl,0.39 mmol), and PTSA (catalytic amount). The reaction was stirred atroom temperature for 4 h and was directly purified by columnchromatography on silica gel (0→100% ethyl acetate in hexane) to yieldthe title compound as an off-white solid (133 mg, 100%).

¹H NMR (600 MHz, CHLOROFORM-d) δ 8.16 (d, J=2.35 Hz, 1H), 7.93 (dd,J=2.35, 8.51 Hz, 1H), 7.89 (s, 1H), 7.62-7.65 (m, 2H), 7.35 (d, J=8.22Hz, 1H), 7.07 (dd, J=2.20, 8.36 Hz, 1H), 3.46 (quin, J=6.53 Hz, 1H),2.44-2.49 (m, 1H), 2.38-2.44 (m, 1H), 2.21 (s, 2H), 2.05-2.11 (m, 1H),1.84-1.90 (m, 1H).

Compound 1084-chloro-N-{5-chloro-2-[(3-hydroxycyclopentyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure D, followed by treatment of the crudeproduct with NaBH₄ in MeOH, the title compound was prepared from4-Chloro-N-[5-chloro-2-(3-oxo-cyclopentylsulfanyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide(Intermediate 35).

1H NMR (600 MHz, CD₃OD) δ 8.13 (d, J=2.05 Hz, 1H), 7.99 (dd, J=2.20,8.36 Hz, 1H), 7.73 (d, J=8.51 Hz, 1H), 7.46 (d, J=8.51 Hz, 1H), 7.34 (d,J=2.05 Hz, 1H), 7.06 (dd, J=2.05, 8.51 Hz, 1H), 4.17-4.22 (m, 1H),3.70-3.77 (m, 1H), 2.19-2.26 (m, 1H), 1.90-2.00 (m, 1H), 1.78-1.86 (m,1H), 1.62-1.76 (m, 2H), 1.29-1.38 (m, 1H).

Compound 1094-chloro-N-[5-chloro-2-(ethylsulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure D, the title compound was prepared from4-chloro-N-[5-chloro-2-(ethylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide.

1H NMR (600 MHz, CD₃OD) δ 8.30 (d, J=1.76 Hz, 1H), 8.14 (dd, J=2.20,8.36 Hz, 1H), 7.72-7.80 (m, 2H), 7.64 (d, J=2.05 Hz, 1H), 7.10 (br. s.,1H), 3.30-3.38 (m, 2H), 1.09 (t, J=7.34 Hz, 3H)

Compound 1102-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylacetamide

Following General Procedure G, the title compound was prepared fromN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide]Intermediate 5 and 2-chloro-N,N-dimethyl-acetamide.

1H NMR (600 MHz, CD₃OD) δ 8.09 (d, J=2.35 Hz, 1H), 7.94 (dd, J=2.05,8.51 Hz, 1H), 7.76 (d, J=8.22 Hz, 1H), 7.47-7.50 (m, 2H), 7.18 (dd,J=2.35, 8.51 Hz, 1H), 3.68 (s, 2H), 2.97 (s, 3H), 2.93 (s, 3H).

Compound 1112-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-methylacetamide

Following General Procedure G, the title compound was prepared fromN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide]Intermediate 5 and 2-chloro-N-methyl-acetamide.

1H NMR (600 MHz, CD₃OD) δ 8.09 (d, J=2.35 Hz, 1H), 7.93 (dd, J=2.35,8.51 Hz, 1H), 7.76 (d, J=8.51 Hz, 1H), 7.48 (d, J=2.35 Hz, 1H), 7.44 (d,J=8.22 Hz, 1H), 7.20 (dd, J=2.35, 8.51 Hz, 1H), 3.40 (s, 2H), 2.69 (s,3H).

Compound 1122-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylacetamide

Following General Procedure C, the title compound was prepared from2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylacetamide.

1H NMR (600 MHz, CD₃OD) δ 8.16 (d, J=2.35 Hz, 1H), 8.01 (dd, J=2.05,8.22 Hz, 1H), 7.68 (d, J=8.51 Hz, 1H), 7.45 (d, J=8.51 Hz, 1H), 7.28 (d,J=1.76 Hz, 1H), 6.90 (dd, J=2.05, 8.22 Hz, 1H), 4.65-4.71 (m, 1H),3.51-3.57 (m, 1H), 3.11 (s, 3H), 2.98 (s, 3H).

Compound 1132-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylacetamide

Following General Procedure D, the title compound was prepared from2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylacetamide.

¹H NMR (600 MHz, CD₃OD) 6 8.29 (d, J=2.05 Hz, 1H), 8.09-8.14 (m, 1H),7.72 (d, J=8.51 Hz, 1H), 7.68 (d, J=8.51 Hz, 1H), 7.48 (d, J=1.76 Hz,1H), 6.81 (d, J=8.22 Hz, 1H), 3.16 (s, 3H), 3.00 (s, 3H).

Compound 1142-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-methylacetamide

Following General Procedure C, the title compound was prepared from2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-methylacetamide.

¹H NMR (600 MHz, CD₃OD) 6 8.15 (d, J=2.05 Hz, 1H), 8.01 (dd, J=2.20,8.36 Hz, 1H), 7.72 (d, J=8.51 Hz, 1H), 7.51 (d, J=8.22 Hz, 1H), 7.22 (d,J=2.05 Hz, 1H), 7.02 (dd, J=1.91, 8.36 Hz, 1H), 4.21 (d, J=13.50 Hz,1H), 3.49 (d, J=13.21 Hz, 1H), 2.76 (s, 3H)

Compound 1152-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N-methylacetamide

Following General Procedure D, the title compound was prepared from2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-methylacetamide.

¹H NMR (600 MHz, CD₃OD) 6 8.29 (d, J=2.05 Hz, 1H), 8.09-8.13 (m, 1H),7.69 (d, J=8.51 Hz, 1H), 7.66 (d, J=8.22 Hz, 1H), 7.44 (d, J=2.05 Hz,1H), 6.75 (dd, J=1.91, 8.66 Hz, 1H), 2.77 (s, 3H).

Compound 116N-{2-[(2-aminoethyl)thio]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure G, the title compound was prepared fromN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide]Intermediate 5 and 2-bromo-ethylamine hydrobromide.

¹H NMR (600 MHz, CD₃OD) δ 8.18 (d, J=2.05 Hz, 1H), 7.99 (dd, J=2.05,8.22 Hz, 1H), 7.65 (d, J=8.51 Hz, 1H), 7.38 (d, J=8.22 Hz, 1H), 7.30 (d,J=2.35 Hz, 1H), 6.72 (dd, J=2.35, 8.22 Hz, 1H), 2.96-3.05 (m, 4H).

Compound 117N-{2-[(2-aminoethyl)sulfonyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure D, followed by treatment of the crudeproduct with excess zinc dust in MeOH, aqueous NH₄Cl and HOAc at roomtemperature for 2 h, the title compound was prepared fromN-{2-[(2-aminoethyl)thio]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide.

¹H NMR (600 MHz, CD₃OD) 6 8.27 (d, J=2.05 Hz, 1H), 8.10 (dd, J=1.91,8.36 Hz, 1H), 7.74 (d, J=8.51 Hz, 1H), 7.67 (d, J=8.51 Hz, 1H), 7.42 (d,J=1.76 Hz, 1H), 6.80 (dd, J=2.05, 8.51 Hz, 1H), 3.88-3.92 (m, 2H),3.45-3.51 (m, 2H).

Compound 118N-{2-[(2-aminoethyl)sulfinyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure C, the title compound was prepared fromN-{2-[(2-aminoethyl)thio]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide.

¹H NMR (300 MHz, CD₃OD) δ 8.15 (d, J=1.76 Hz, 1H), 8.00 (dd, J=1.90,8.35 Hz, 1H), 7.69 (d, J=8.21 Hz, 1H), 7.46 (d, J=8.50 Hz, 1H), 7.25 (d,J=2.05 Hz, 1H), 6.94 (dd, J=1.90, 8.35 Hz, 1H), 3.53-3.67 (m, 1H),3.36-3.50 (m, 1H), 3.17-3.31 (m, 2H).

Compound 1193-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)-N,N-dimethylpropanamide

Following General Procedure O, the title compound was prepared fromN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide)Intermediate 8 and N,N-dimethyl-acrylamide.

¹H NMR (600 MHz, CD₃OD) δ 7.69 (d, J=7.92 Hz, 1H), 7.53-7.56 (m, 1H),7.45-7.49 (m, 2H), 7.39 (s, 1H), 7.37 (d, J=8.51 Hz, 1H), 7.31-7.35 (m,1H), 7.17-7.20 (m, 1H), 2.90 (t, J=7.19 Hz, 2H), 2.87 (s, 3H), 2.85 (s,3H), 2.33 (t, J=7.19 Hz, 2H).

Compound 1203-({2-[(1-benzofuran-2-yl)sulfonyl)amino]-4-chlorophenyl}sulfinyl)-N,N-dimethylpropanamide

Following General Procedure C, the title compound was prepared from3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)-N,N-dimethylpropanamide.

¹H NMR (600 MHz, CD₃OD) δ 7.72 (d, J=7.34 Hz, 1H), 7.64 (d, J=8.22 Hz,1H), 7.58 (d, J=8.51 Hz, 1H), 7.46-7.51 (m, 1H), 7.46 (s, 1H), 7.39 (d,J=1.76 Hz, 1H), 7.32-7.37 (m, 2H), 3.27-3.34 (m, 1H), 3.16-3.24 (m, 1H),2.96 (s, 3H), 2.90 (s, 3H), 2.77-2.86 (m, 1H), 2.59-2.66 (m, 1H).

Compound 1213-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)-N,N-dimethylpropanamide

Following General Procedure D, the title compound was prepared from3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)-N,N-dimethylpropanamide.

¹H NMR (300 MHz, CD₃OD) δ 7.59-7.75 (m, 3H), 7.40-7.49 (m, 1H),7.30-7.41 (m, 1H), 7.20-7.30 (m, 2H), 6.79 (dd, J=1.76, 8.50 Hz, 1H),3.94 (t, J=7.47 Hz, 2H), 2.87 (s, 3H), 2.81 (s, 3H), 2.59 (t, J=7.47 Hz,2H).

Compound 122N-(2-{[(6-amino-1-oxidopyridin-2-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D and E, the title compound was preparedfromtert-butyl{6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.

¹H NMR (300 MHz, CD₃OD) δ 7.77 (d, J=1.76 Hz, 1H), 7.59-7.71 (m, 2H),7.29-7.44 (m, 3H), 7.20-7.29 (m, 1H), 7.10 (t, J=7.91 Hz, 1H), 6.77-6.88(m, 2H), 6.57 (d, J=7.33 Hz, 1H), 5.41 (br. s., 2H), 4.57 (br. s., 1H).

General Procedure P Compound 123N-(2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}ethyl)acetamide

To a solution ofN-{2-[(2-aminoethyl)sulfonyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide(23 mg, 0.048 mmol) in CH₂Cl₂ (2 ml) was added Et₃N (14 μl, 0.10 mmol),acetic anhydride (5 μl, 0.053 mmol), and catalytic amount of DMAP. Thereaction was stirred at room temperature for 1 h and was concentrated.The crude product was purified by column chromatography on silica gel(0→10% MeOH in ethyl acetate), followed by PTLC (10% MeOH in ethylacetate) to give the title compound.

¹H NMR (600 MHz, CD₃OD) 6 8.29 (d, J=2.05 Hz, 1H), 8.13 (dd, J=2.05,8.51 Hz, 1H), 7.65-7.75 (m, 2H), 7.51 (d, J=2.05 Hz, 1H), 6.82 (dd,J=2.05, 8.51 Hz, 1H), 3.75 (t, J=6.60 Hz, 2H), 3.51 (t, J=6.60 Hz, 2H),1.86 (s, 3H).

Compound 124N-(2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}ethyl)acetamide

Following General Procedure P and C, the title compound was preparedfromN-{2-[(2-aminoethyl)thio]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide.

¹H NMR (600 MHz, CD₃OD) δ 8.12 (s, 1H), 8.01 (dd, J=1.91, 8.36 Hz, 1H),7.77 (d, J=8.51 Hz, 1H), 7.56 (d, J=8.22 Hz, 1H), 7.17 (s, 1H), 7.13 (d,J=7.63 Hz, 1H), 3.60-3.71 (m, 1H), 3.44-3.54 (m, 1H), 3.33-3.42 (m, 1H),3.04-3.15 (m, 1H), 1.98 (s, 3H).

Intermediate 36 4-Chloro-N,N-dimethyl-butyramide

To a solution of 4-chloro-butyryl chloride (1.12 ml, 10.0 mmol) anddimethyl-amine hydrochloride (4.1 g, 50.0 mmol) in THF at 5° C. wasadded 2M NaOH (30 ml, 60.0 mmol) dropwise over 30 minutes whilemaintaining reaction temperature between 5-10° C. The reaction wasstirred for additional 1.5 h and was concentrated, extracted with EtOAc(x2). The combined organic layer was washed with 1M HCl (×2), brine,dried over Na₂SO₄, and concentrated in vacuo to yield the title compoundas colorless oil (1.5 g, ˜100%). The crude was used without furtherpurification.

Compound 1254-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)-N,N-dimethylbutanamide

Following General Procedure G and C, the title compound was preparedfromN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide)Intermediate 8 and 4-chloro-N,N-dimethyl-butyramide.

¹H NMR (300 MHz, CD₃OD) δ 7.68 (d, J=7.62 Hz, 1H), 7.53 (d, J=2.05 Hz,1H), 7.35-7.49 (m, 3H), 7.32 (d, J=0.88 Hz, 1H), 7.25-7.32 (m, 1H), 6.95(dd, J=2.05, 8.20 Hz, 1H), 3.33-3.49 (m, 1H), 2.98 (s, 3H), 2.91-3.08(m, 1H), 2.90 (s, 3H), 2.38-2.57 (m, 2H), 1.92-2.09 (m, 2H).

Compound 1264-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)-N,N-dimethylbutanamide

Following General Procedure G and D, the title compound was preparedfromN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide)Intermediate 8 and 4-chloro-N,N-dimethyl-butyramide.

¹H NMR (600 MHz, CD₃OD) δ 7.76 (s, 1H), 7.74 (d, J=8.51 Hz, 1H), 7.70(d, J=7.92 Hz, 1H), 7.38-7.48 (m, 3H), 7.31 (t, J=7.34 Hz, 1H),6.86-7.05 (m, 1H), 3.46-3.69 (m, 2H), 2.97 (s, 3H), 2.91 (s, 3H),2.43-2.59 (m, 2H), 1.93-2.09 (m, 2H).

Compound 1275-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide

Following General Procedure B and C, the title compound was preparedfrom 5-chloro-2-(methylthio)aniline and 5-chloro-benzofuran-2-sulfonylchloride (CAS #: 128852-02-8) (Bioorganic & Medicinal Chemistry 13(2005) 3927-3954).

¹H NMR (300 MHz, CDCl₃) δ 11.00 (br. s., 1H), 7.80 (d, J=1.47 Hz, 1H),7.68 (d, J=1.76 Hz, 1H), 7.40-7.54 (m, 3H), 7.05-7.16 (m, 2H), 2.91 (s,3H).

Compound 1285-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide

Following General Procedure B and D, the title compound was preparedfrom 5-chloro-2-(methylthio)aniline and 5-chloro-benzofuran-2-sulfonylchloride (CAS #: 128852-02-8) (Bioorganic & Medicinal Chemistry 13(2005) 3927-3954).

¹H NMR (600 MHz, CD₃OD) δ 7.74 (s, 1H), 7.74 (d, J=5.58 Hz, 1H), 7.64(d, J=1.76 Hz, 1H), 7.43 (d, J=8.80 Hz, 1H), 7.30-7.35 (m, 2H), 6.88(dd, J=2.05, 8.51 Hz, 1H), 3.33 (s, 3H).

Compound 129N-{5-chloro-2-[(1H-pyrazol-3-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C and E, the title compound was preparedfrom tert-butyl3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1H-pyrazole-1-carboxylate(Compound 22).

¹H NMR (600 MHz, CD₃OD) δ 7.67 (d, J=7.63 Hz, 1H), 7.42-7.47 (m, 2H),7.41 (d, J=2.05 Hz, 1H), 7.37 (td, J=1.47, 7.78 Hz, 1H), 7.32 (d, J=0.88Hz, 1H), 7.28 (td, J=0.88, 7.48 Hz, 1H), 7.22 (d, J=8.51 Hz, 1H), 6.96(dd, J=1.76, 8.51 Hz, 1H), 5.92 (s, 1H), 4.56 (d, J=13.50 Hz, 1H), 4.28(d, J=13.50 Hz, 1H).

Compound 130N-[5-chloro-2-(methylsulfinyl)phenyl]-4-isopropylbenzenesulfonamide

Following General Procedure B and C, the title compound was preparedfrom 5-chloro-2-(methylthio)aniline and 4-isopropyl-benzenesulfonylchloride.

¹H NMR (600 MHz, CHLOROFORM-d) δ 10.42 (br. s., 1H), 7.80-7.86 (m, 2H),7.68 (s, 1H), 7.35 (s, 2H), 7.05-7.08 (m, 1H), 7.01-7.03 (m, 1H), 2.94(spt, J=6.90 Hz, 1H), 2.69 (s, 3H), 1.22 (d, J=7.04 Hz, 6H).

Compound 131 4-bromo-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide

Following General Procedure B, the title compound was prepared from5-chloro-2-(methylthio)aniline and 4-bromo-benzenesulfonyl chloride.

¹H NMR (600 MHz, CHLOROFORM-d) δ 7.65-7.68 (m, 2H), 7.61-7.63 (m, 2H),7.58-7.60 (m, 2H), 7.29 (d, J=8.22 Hz, 1H), 7.04 (dd, J=2.20, 8.36 Hz,1H), 2.17 (s, 3H).

Compound 132 N-[5-chloro-2-(methylthio)phenyl]-4-iodobenzenesulfonamide

Following General Procedure B, the title compound was prepared from5-chloro-2-(methylthio)aniline and 4-iodo-benzenesulfonyl chloride.

¹H NMR (600 MHz, CHLOROFORM-d) δ 7.80 (d, J=8.80 Hz, 2H), 7.62-7.64 (m,1H), 7.61 (d, J=2.05 Hz, 1H), 7.49-7.53 (m, 2H), 7.30 (d, J=8.22 Hz,1H), 7.04 (dd, J=2.20, 8.36 Hz, 1H), 2.17 (s, 3H).

Compound 1334-bromo-N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide

Following General Procedure C, the title compound was prepared from4-bromo-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide.

¹H NMR (600 MHz, CHLOROFORM-d) δ 10.63-10.77 (m, 1H), 7.79-7.82 (m, 2H),7.64-7.68 (m, 3H), 7.05 (dd, J=1.17, 2.35 Hz, 2H), 2.79 (s, 3H).

Compound 134N-[5-chloro-2-(methylsulfinyl)phenyl]-4-iodobenzenesulfonamide

Following General Procedure C, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]-4-iodobenzenesulfonamide.

¹H NMR (600 MHz, CHLOROFORM-d) δ 10.69 (br. s., 1H), 7.83-7.91 (m, 2H),7.61-7.69 (m, 3H), 7.01-7.08 (m, 2H), 2.79 (s, 3H).

Compound 1354-bromo-N-[5-chloro-2-(methylsulfonyl)phenyl]benzenesulfonamide

Following General Procedure D, the title compound was prepared from4-bromo-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide.

¹H NMR (600 MHz, CHLOROFORM-d) δ 9.20-9.27 (m, 1H), 7.80 (dd, J=1.32,8.36 Hz, 2H), 7.76 (d, J=8.51 Hz, 1H), 7.68 (dd, J=1.47, 8.80 Hz, 2H),7.25 (d, J=1.47 Hz, 1H), 7.18-7.21 (m, 1H), 2.93 (d, J=1.47 Hz, 3H).

Compound 136N-[5-chloro-2-(methylsulfonyl)phenyl]-4-iodobenzenesulfonamide

Following General Procedure D, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]-4-iodobenzenesulfonamide.

¹H NMR (600 MHz, CHLOROFORM-d) δ 9.17-9.25 (m, 1H), 7.90 (d, J=8.51 Hz,2H), 7.76 (d, J=8.51 Hz, 1H), 7.67 (d, J=1.76 Hz, 1H), 7.64 (d, J=8.51Hz, 2H), 7.19 (dd, J=1.76, 8.51 Hz, 1H), 2.93 (s, 3H).

Compound 137N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure A and B, the title compound was preparedfrom 2-amino-4-chloro-benzenethiol, 2-bromomethyl-pyridine hydrobromide,and benzofuran-2-sulfonyl chloride.

¹H NMR (600 MHz, CHLOROFORM-d) δ 12.32 (br. s, 1H), 8.87 (dt, J=0.77,4.92 Hz, 1H), 7.76 (d, J=2.05 Hz, 1H), 7.58-7.65 (m, 2H), 7.44 (dd,J=0.88, 8.22 Hz, 1H), 7.34-7.42 (m, 3H), 7.25-7.30 (m, 2H), 7.06 (d,J=7.63 Hz, 1H), 6.96-7.01 (m, 1H), 3.98 (s, 2H).

Compound 138N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure A and B, the title compound was preparedfrom 2-amino-4-chloro-benzenethiol, 3-bromomethyl-pyridine hydrobromide,and benzofuran-2-sulfonyl chloride.

¹H NMR (600 MHz, CHLOROFORM-d) δ 8.42 (dd, J=1.61, 4.84 Hz, 1H), 8.12(d, J=1.76 Hz, 2H), 7.66-7.70 (m, 2H), 7.50 (d, J=1.17 Hz, 1H),7.46-7.49 (m, 1H), 7.42-7.46 (m, 1H), 7.33 (ddd, J=1.17, 6.97, 8.00 Hz,1H), 7.26-7.29 (m, 1H), 7.13 (ddd, J=0.88, 4.70, 7.92 Hz, 1H), 7.00 (d,J=8.51 Hz, 1H), 6.89 (dd, J=2.20, 8.36 Hz, 1H), 3.75 (s, 2H).

Compound 139N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound was prepared fromN-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, METHANOL-d₄) δ 8.28 (d, J=4.11 Hz, 1H), 7.86 (br. s.,1H), 7.68-7.71 (m, J=0.73, 1.32 Hz, 1H), 7.54 (d, J=1.76 Hz, 1H),7.36-7.41 (m, 2H), 7.31-7.35 (m, 1H), 7.25-7.29 (m, J=1.03, 7.78 Hz,1H), 7.24 (d, J=7.92 Hz, 1H), 7.12 (dd, J=4.99, 7.63 Hz, 1H), 6.73 (d,J=8.51 Hz, 1H), 6.68 (dd, J=2.05, 8.51 Hz, 1H), 4.55 (s, 2H).

Compound 140N-(5-chloro-2-{[(1-oxidopyridin-3-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound was prepared fromN-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, METHANOL-d₄) δ 8.10-8.14 (m, 1H), 8.01 (t, J=1.47 Hz,1H), 7.66-7.68 (m, 1H), 7.42-7.49 (m, 2H), 7.34 (ddd, J=1.17, 7.12, 8.44Hz, 1H), 7.23-7.29 (m, 2H), 7.14 (dd, J=6.60, 7.78 Hz, 1H), 6.87 (d,J=7.92 Hz, 1H), 6.83 (d, J=8.22 Hz, 1H), 6.71 (dd, J=2.05, 8.22 Hz, 1H),4.63 (d, J=13.21 Hz, 1H), 4.37 (d, J=13.21 Hz, 1H).

Compound 141N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, METHANOL-d₄) δ 8.27 (d, J=4.11 Hz, 1H), 8.04 (br. s.,1H), 7.78 (t, J=1.76 Hz, 1H), 7.65 (d, J=7.92 Hz, 1H), 7.46 (d, J=0.88Hz, 1H), 7.31-7.37 (m, 2H), 7.27-7.31 (m, 1H), 7.21-7.26 (m, 2H), 7.06(dd, J=5.14, 7.48 Hz, 1H), 6.67 (dt, J=1.76, 8.51 Hz, 1H), 4.98 (s, 2H).

Compound 142N-(5-chloro-2-{[(1-oxidopyridin-3-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, DMSO-d₆) δ 8.01-8.08 (m, 2H), 7.68 (d, J=7.92 Hz, 1H),7.53 (d, J=8.22 Hz, 1H), 7.46-7.48 (m, 1H), 7.31-7.37 (m, 2H), 7.23-7.27(m, 2H), 7.11-7.15 (m, 1H), 6.98 (d, J=7.92 Hz, 1H), 6.58-6.61 (m, 1H),5.09 (s, 2H).

Compound 143N-{5-chloro-2-[(3-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure G, the title compound was prepared fromN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide)Intermediate 8 and 1-bromomethyl-3-nitro-benzene.

¹H NMR (600 MHz, CHLOROFORM-d) δ 8.08 (s, 1H), 8.02 (ddd, J=1.17, 2.35,8.22 Hz, 1H), 7.77 (t, J=2.05 Hz, 1H), 7.65-7.69 (m, 2H), 7.50 (d,J=0.88 Hz, 1H), 7.45-7.48 (m, 1H), 7.41-7.45 (m, 1H), 7.30-7.36 (m, 2H),7.21 (dq, J=0.88, 7.63 Hz, 1H), 7.03 (d, J=8.22 Hz, 1H), 6.89 (dd,J=2.05, 8.22 Hz, 1H), 3.84 (s, 2H).

Compound 144N-{5-chloro-2-[(3-methoxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure G, the title compound was prepared fromN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide)Intermediate 8 and 1-bromomethyl-3-methoxy-benzene.

¹H NMR (600 MHz, CHLOROFORM-d) δ 8.11 (s, 1H), 7.64-7.68 (m, 2H),7.40-7.50 (m, 3H), 7.31 (ddd, J=0.88, 7.04, 7.92 Hz, 1H), 7.07-7.13 (m,2H), 6.90 (dd, J=2.05, 8.22 Hz, 1H), 6.73 (ddd, J=1.17, 2.49, 8.36 Hz,1H), 6.53-6.56 (m, 1H), 6.48 (t, J=2.35 Hz, 1H), 3.74 (s, 2H), 3.66 (s,3H).

Compound 145N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound was prepared fromN-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, METHANOL-d₄) δ 8.46 (d, J=4.70 Hz, 1H), 7.64-7.73 (m,2H), 7.48 (d, J=8.51 Hz, 1H), 7.38-7.45 (m, 3H), 7.25-7.34 (m, 3H),7.07-7.17 (m, 2H), 4.58 (d, J=12.91 Hz, 1H), 4.35 (d, J=12.91 Hz, 1H).

Compound 146N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, METHANOL-d₄) δ 8.42 (dt, J=0.84, 4.77 Hz, 1H), 7.75 (d,J=2.05 Hz, 1H), 7.67 (d, J=7.63 Hz, 1H), 7.41-7.49 (m, 3H), 7.31-7.39(m, 2H), 7.22-7.29 (m, 2H), 7.07 (d, J=7.63 Hz, 1H), 6.76 (dd, J=1.91,8.66 Hz, 1H), 5.07 (s, 2H).

Compound 147N-(5-chloro-2-{[(1-oxidopyridin-2-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

¹H NMR (600 MHz, METHANOL-d₄) δ 8.35 (d, J=6.46 Hz, 1H), 7.74 (d, J=2.05Hz, 1H), 7.66 (d, J=7.92 Hz, 1H), 7.60 (d, J=8.51 Hz, 1H), 7.38 (s, 2H),7.34 (d, J=10.56 Hz, 3H), 7.25 (s, 2H), 6.77 (dd, J=1.32, 8.36 Hz, 1H),5.54 (br. s, 2H).

Compound 148N-(5-chloro-2-{[(1-oxidopyridin-2-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

¹H NMR (600 MHz, METHANOL-d₄) δ 8.31 (d, J=6.16 Hz, 1H), 7.66 (d, J=7.92Hz, 1H), 7.46-7.50 (m, 1H), 7.38-7.42 (m, 1H), 7.30-7.38 (m, 2H), 7.28(s, 3H), 7.19 (d, J=8.51 Hz, 1H), 7.05 (d, J=7.63 Hz, 1H), 6.82 (d,J=8.22 Hz, 1H), 5.14 (d, J=12.62 Hz, 1H), 4.68 (d, J=12.32 Hz, 1H).

Compound 149N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-1-benzofuran-2-sulfonamide

Following General Procedure L, the title compound was prepared fromN-{5-chloro-2-[(3-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, CHLOROFORM-d) δ 7.64-7.68 (m, 2H), 7.47-7.51 (m, 1H),7.40-7.46 (m, 2H), 7.29-7.34 (m, 1H), 7.14 (d, J=8.22 Hz, 1H), 6.97 (t,J=7.78 Hz, 1H), 6.92 (dd, J=2.35, 8.22 Hz, 1H), 6.48-6.52 (m, 1H), 6.35(dd, J=0.59, 7.63 Hz, 1H), 6.28 (t, J=1.91 Hz, 1H), 3.67 (s, 2H).

Compound 150N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C and K, the title compound was preparedfromN-{5-chloro-2-[(3-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, METHANOL-d₄) δ 7.69 (d, J=7.92 Hz, 1H), 7.48 (d, J=8.51Hz, 1H), 7.37-7.43 (m, 3H), 7.30 (td, J=0.88, 7.48 Hz, 1H), 7.20 (d,J=8.51 Hz, 1H), 7.01 (dd, J=2.05, 8.51 Hz, 1H), 6.95 (t, J=7.78 Hz, 1H),6.70-6.74 (m, 1H), 6.64 (t, J=1.76 Hz, 1H), 6.45 (d, J=7.63 Hz, 1H),4.40 (d, J=12.62 Hz, 1H), 4.00 (d, J=12.62 Hz, 1H).

Compound 151N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D and K, the title compound was preparedfromN-{5-chloro-2-[(3-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, METHANOL-d₄) δ 7.80 (d, J=2.05 Hz, 1H), 7.69 (d, J=7.63Hz, 1H), 7.52 (d, J=0.59 Hz, 1H), 7.40 (d, J=8.51 Hz, 1H), 7.35 (td,J=1.32, 7.70 Hz, 1H), 7.31 (d, J=8.51 Hz, 1H), 7.26-7.30 (m, J=7.92 Hz,1H), 6.78 (dd, J=2.05, 8.51 Hz, 1H), 6.65 (t, J=7.78 Hz, 1H), 6.49 (dd,J=1.91, 7.78 Hz, 1H), 6.33 (t, J=1.76 Hz, 1H), 6.05 (d, J=7.34 Hz, 1H),4.66 (s, 2H).

Compound 152N-{5-chloro-2-[(3-hydroxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide

To a solution ofN-{5-chloro-2-[(3-methoxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide(315 mg, 0.69 mmol) in CH₂Cl₂ (5 ml) at room temperature was added BBr₃(1 M solution in CH₂Cl₂, 2.1 ml, 2.1 mmol) and the reaction was stirredfor 2 h, diluted with EtOAc, washed with brine, dried over Na₂SO₄,concentrated in vacuo. The crude product was purified by columnchromatography on silica gel (25% ethyl acetate in hexane) to give thetitle compound (196 mg, 64%).

¹H NMR (600 MHz, CHLOROFORM-d) δ 8.10 (br. s., 1H), 7.63-7.69 (m, 2H),7.41-7.51 (m, 3H), 7.32 (td, J=0.88, 7.48 Hz, 1H), 7.12 (d, J=8.22 Hz,1H), 7.05 (t, J=7.92 Hz, 1H), 6.91 (dd, J=2.35, 8.22 Hz, 1H), 6.66 (ddd,J=0.73, 2.57, 8.14 Hz, 1H), 6.51 (d, J=7.92 Hz, 1H), 6.45-6.48 (m, 1H),5.07 (br. s., 1H), 3.71 (s, 2H).

Compound 153N-{5-chloro-2-[(3-hydroxybenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound was prepared fromN-{5-chloro-2-[(3-hydroxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide

¹H NMR (600 MHz, CHLOROFORM-d) δ 10.27-11.14 (m, 1H), 7.73 (d, J=2.05Hz, 1H), 7.67 (d, J=7.92 Hz, 1H), 7.53 (s, 1H), 7.43-7.47 (m, 1H),7.38-7.42 (m, 1H), 7.28-7.33 (m, 1H), 7.04 (t, J=7.92 Hz, 1H), 6.92 (dd,J=1.47, 8.22 Hz, 1H), 6.79 (d, J=8.22 Hz, 1H), 6.74 (dd, J=2.05, 8.22Hz, 1H), 6.59 (s, 1H), 6.40 (d, J=7.34 Hz, 1H), 4.33 (d, J=12.32 Hz,1H), 4.16 (d, J=12.62 Hz, 1H).

Compound 154N-{5-chloro-2-[(3-hydroxybenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-{5-chloro-2-[(3-hydroxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide

¹H NMR (600 MHz, CHLOROFORM-d) δ 7.76 (br. s., 1H), 7.65-7.72 (m, 1H),7.56 (br. s., 1H), 7.44 (br. s., 3H), 7.33 (s, 1H), 7.02 (br. s., 2H),6.77 (br. s., 1H), 6.58 (br. s., 1H), 6.39-6.47 (m, 1H), 4.28 (br. s.,2H).

Intermediate 37 benzofuran-2-sulfonic acid(5-chloro-2-mercapto-phenyl)-amide

Following General Procedure N, the title compound was prepared fromN,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide)Intermediate 8 and was used without further purification.

Compound 155N-{5-chloro-2-[(trifluoromethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

To a solution of benzofuran-2-sulfonic acid(5-chloro-2-mercapto-phenyl)-amide (332 mg, 0.98 mmol) in CH₂Cl₂ (10 ml)at −78° C. was added 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole(CAS #: 887144-97-0, 354 mg, 1.07 mmol) and the reaction was stirred for1 h, and was concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel (CH₂Cl₂) to give the title compound(375 mg, 94%).

¹H NMR (600 MHz, CHLOROFORM-d) δ 7.88 (s, 1H), 7.82 (d, J=2.05 Hz, 1H),7.67 (dd, J=0.59, 7.92 Hz, 1H), 7.49-7.54 (m, 3H), 7.44-7.49 (m, 1H),7.33 (td, J=1.03, 7.56 Hz, 1H), 7.11 (dd, J=2.20, 8.36 Hz, 1H).

Compound 156N-{5-chloro-2-[(trifluoromethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D using 10 equivalents of mCPBA in refluxingCH₂Cl₂, the title compound was prepared fromN-{5-chloro-2-[(trifluoromethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, acetone-d6) δ 7.90 (d, J=2.05 Hz, 1H), 7.78 (d, J=8.80Hz, 1H), 7.71 (d, J=7.92 Hz, 1H), 7.51 (d, J=8.22 Hz, 1H), 7.36-7.43 (m,2H), 7.29 (t, J=7.48 Hz, 1H), 6.92 (d, J=6.46 Hz, 1H).

Compound 157N-{5-chloro-2-[(trifluoromethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D using 10 equivalents of mCPBA in refluxingCH₂Cl₂, the title compound was prepared fromN-{5-chloro-2-[(trifluoromethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, acetone-d6) δ 10.00 (br. s., 1H), 7.89 (d, J=8.22 Hz,1H), 7.78-7.81 (m, 1H), 7.63-7.66 (m, 1H), 7.50-7.59 (m, 4H), 7.39 (ddd,J=0.88, 7.26, 8.00 Hz, 1H).

Compound 158N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-2,4-difluorobenzenesulfonamide

Following General Procedure A, B, and K, the title compound was preparedfrom 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and2,4-difluoro-benzenesulfonyl chloride.

¹H NMR (600 MHz, CHLOROFORM-d) δ 7.92 (td, J=6.16, 8.51 Hz, 1H), 7.47(d, J=2.35 Hz, 1H), 7.19 (d, J=8.22 Hz, 1H), 7.01-7.06 (m, 1H),6.95-7.01 (m, 1H), 6.88-6.94 (m, 2H), 6.57 (dd, J=1.47, 8.80 Hz, 1H),6.40-6.45 (m, 2H), 3.72 (s, 2H).

Compound 159N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-2,4-difluorobenzenesulfonamide

Following General Procedure A, B, D, and K, the title compound wasprepared from 2-amino-4-chloro-benzenethiol,1-bromomethyl-3-nitro-benzene, and 2,4-difluoro-benzenesulfonylchloride.

¹H NMR (600 MHz, METHANOL-d₄) δ 8.05 (td, J=6.16, 8.51 Hz, 1H),7.48-7.54 (m, 2H), 7.14-7.25 (m, 2H), 7.09 (dd, J=2.05, 8.51 Hz, 1H),6.96 (t, J=7.78 Hz, 1H), 6.66-6.71 (m, 1H), 6.54 (t, J=1.91 Hz, 1H),6.34 (d, J=7.63 Hz, 1H), 4.44 (s, 2H).

Compound 160N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-4-chloro-2-fluorobenzenesulfonamide

Following General Procedure A, B, D, and K, the title compound wasprepared from 2-amino-4-chloro-benzenethiol,1-bromomethyl-3-nitro-benzene, and 4-chloro-2-fluoro-benzenesulfonylchloride.

¹H NMR (600 MHz, METHANOL-d₄) δ 7.97 (t, J=8.51 Hz, 1H), 7.54 (d, J=8.51Hz, 1H), 7.43-7.52 (m, 3H), 7.13-7.17 (m, 1H), 6.98 (t, J=7.78 Hz, 1H),6.67-6.72 (m, 1H), 6.53 (s, 1H), 6.33 (d, J=7.63 Hz, 1H), 4.42 (s, 2H).

Compound 161N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-4-chloro-2-fluorobenzenesulfonamide

Following General Procedure A, B, C, and K, the title compound wasprepared from 2-amino-4-chloro-benzenethiol,1-bromomethyl-3-nitro-benzene, and 4-chloro-2-fluoro-benzenesulfonylchloride.

¹H NMR (600 MHz, METHANOL-d₄) δ 7.85 (t, J=8.07 Hz, 1H), 7.49 (dd,J=1.76, 9.98 Hz, 1H), 7.40 (dd, J=1.91, 8.36 Hz, 1H), 7.33 (d, J=8.22Hz, 1H), 7.23 (dd, J=1.91, 8.36 Hz, 1H), 7.16 (d, J=2.05 Hz, 1H), 7.04(t, J=7.78 Hz, 1H), 6.72-6.75 (m, 1H), 6.63 (t, J=1.91 Hz, 1H), 6.50 (d,J=7.34 Hz, 1H), 4.30 (d, J=12.91 Hz, 1H), 4.04 (d, J=12.62 Hz, 1H).

Compound 162N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}benzenesulfonamide

Following General Procedure A, B, and K, the title compound was preparedfrom 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, andbenzenesulfonyl chloride.

¹H NMR (600 MHz, METHANOL-d₄) δ 7.75-7.79 (m, 2H), 7.57-7.62 (m, 1H),7.48-7.53 (m, 2H), 7.44 (d, J=2.05 Hz, 1H), 7.14 (d, J=8.22 Hz, 1H),6.99 (dd, J=2.35, 8.22 Hz, 1H), 6.95 (t, J=7.78 Hz, 1H), 6.56-6.60 (m,1H), 6.45 (t, J=1.91 Hz, 1H), 6.35 (d, J=7.34 Hz, 1H), 3.58 (s, 2H).

Compound 163N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-4-chlorobenzenesulfonamide

Following General Procedure A, B, and K, the title compound was preparedfrom 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and4-chloro-benzenesulfonyl chloride.

¹H NMR (600 MHz, CHLOROFORM-d) δ 7.69-7.72 (m, 2H), 7.54 (d, J=2.35 Hz,1H), 7.40-7.44 (m, 2H), 7.17 (d, J=8.22 Hz, 1H), 7.03 (t, J=7.78 Hz,1H), 6.95 (dd, J=2.20, 8.36 Hz, 1H), 6.58 (dd, J=1.76, 7.92 Hz, 1H),6.34-6.39 (m, 2H), 3.61 (s, 2H).

Compound 164N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-3-chlorobenzenesulfonamide

Following General Procedure A, B, and K, the title compound was preparedfrom 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and3-chloro-benzenesulfonyl chloride.

¹H NMR (600 MHz, CHLOROFORM-d) δ 7.80 (t, J=1.91 Hz, 1H), 7.63-7.66 (m,1H), 7.56 (d, J=2.35 Hz, 1H), 7.52 (ddd, J=0.88, 1.98, 8.00 Hz, 1H),7.39 (t, J=7.92 Hz, 1H), 7.16 (d, J=8.51 Hz, 1H), 7.02 (t, J=7.78 Hz,1H), 6.96 (dd, J=2.05, 8.22 Hz, 1H), 6.55-6.59 (m, 1H), 6.35 (d, J=7.63Hz, 1H), 6.32 (t, J=1.91 Hz, 1H), 3.56 (s, 2H).

Compound 165N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}benzenesulfonamide

Following General Procedure A, B, D, and K, the title compound wasprepared from 2-amino-4-chloro-benzenethiol,1-bromomethyl-3-nitro-benzene, and benzenesulfonyl chloride.

¹H NMR (600 MHz, METHANOL-d₄) δ 7.90-7.93 (m, 2H), 7.63-7.68 (m, 1H),7.56-7.62 (m, 3H), 7.42 (d, J=8.51 Hz, 1H), 7.11 (dd, J=2.05, 8.51 Hz,1H), 6.93 (t, J=7.78 Hz, 1H), 6.66 (ddd, J=0.73, 2.27, 8.14 Hz, 1H),6.39 (t, J=1.91 Hz, 1H), 6.16 (d, J=7.34 Hz, 1H), 4.18 (s, 2H).

Compound 166N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}benzenesulfonamide

Following General Procedure A, B, C, and K, the title compound wasprepared from 2-amino-4-chloro-benzenethiol,1-bromomethyl-3-nitro-benzene, and benzenesulfonyl chloride.

¹H NMR (600 MHz, METHANOL-d₄) δ 7.82-7.86 (m, 2H), 7.64-7.69 (m, 1H),7.56-7.62 (m, 2H), 7.27-7.31 (m, 1H), 7.22-7.27 (m, 1H), 7.08 (d, J=2.05Hz, 1H), 6.99 (t, J=7.78 Hz, 1H), 6.67 (ddd, J=0.88, 2.35, 8.22 Hz, 1H),6.50 (t, J=1.91 Hz, 1H), 6.36 (d, J=7.63 Hz, 1H), 4.12 (d, J=12.62 Hz,1H), 3.95 (d, J=12.91 Hz, 1H).

Compound 167N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-4-chlorobenzenesulfonamide

Following General Procedure A, B, D, and K, the title compound wasprepared from 2-amino-4-chloro-benzenethiol,1-bromomethyl-3-nitro-benzene, and 4-chloro-benzenesulfonyl chloride.

¹H NMR (600 MHz, METHANOL-d₄) δ 7.85-7.88 (m, 2H), 7.58-7.62 (m, 2H),7.55 (d, J=2.05 Hz, 1H), 7.49 (d, J=8.51 Hz, 1H), 7.15 (dd, J=1.91, 8.66Hz, 1H), 6.95 (t, J=7.78 Hz, 1H), 6.68 (ddd, J=0.88, 2.20, 8.07 Hz, 1H),6.45 (t, J=1.91 Hz, 1H), 6.21 (d, J=7.63 Hz, 1H), 4.28 (s, 2H).

Compound 168N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-4-chlorobenzenesulfonamide

Following General Procedure A, B, C, and K, the title compound wasprepared from 2-amino-4-chloro-benzenethiol,1-bromomethyl-3-nitro-benzene, and 4-chloro-benzenesulfonyl chloride.

¹H NMR (600 MHz, METHANOL-d₄) δ 7.79 (d, J=8.51 Hz, 2H), 7.59 (d, J=8.80Hz, 2H), 7.32 (d, J=8.51 Hz, 1H), 7.24-7.29 (m, 1H), 7.06 (d, J=1.76 Hz,1H), 6.99 (t, J=7.78 Hz, 1H), 6.65-6.69 (m, 1H), 6.52 (s, 1H), 6.38 (d,J=7.34 Hz, 1H), 4.16 (d, J=12.91 Hz, 1H), 3.97 (d, J=12.91 Hz, 1H).

Compound 169N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-3-chlorobenzenesulfonamide

Following General Procedure A, B, D, and K, the title compound wasprepared from 2-amino-4-chloro-benzenethiol,1-bromomethyl-3-nitro-benzene, and 3-chloro-benzenesulfonyl chloride.

¹H NMR (600 MHz, METHANOL-d₄) δ 8.00 (t, J=1.91 Hz, 1H), 7.89-7.93 (m,1H), 7.42-7.51 (m, 3H), 7.38 (d, J=8.51 Hz, 1H), 6.89 (t, J=7.78 Hz,1H), 6.66 (dd, J=1.76, 8.51 Hz, 1H), 6.59 (d, J=8.22 Hz, 1H), 6.55 (s,1H), 6.37 (d, J=7.63 Hz, 1H), 4.69 (s, 2H).

Compound 170N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-3-chlorobenzenesulfonamide

Following General Procedure A, B, C, and K, the title compound wasprepared from 2-amino-4-chloro-benzenethiol,1-bromomethyl-3-nitro-benzene, and 3-chloro-benzenesulfonyl chloride.

¹H NMR (600 MHz, METHANOL-d₄) δ 7.85 (s, 1H), 7.77 (d, J=7.63 Hz, 1H),7.51-7.55 (m, 1H), 7.47 (t, J=7.92 Hz, 1H), 7.22 (d, J=8.22 Hz, 1H),7.19 (d, J=1.76 Hz, 1H), 6.93-7.00 (m, 2H), 6.65 (dd, J=2.20, 8.07 Hz,1H), 6.58 (s, 1H), 6.43 (d, J=7.63 Hz, 1H), 4.35 (d, J=12.91 Hz, 1H),3.82 (d, J=12.91 Hz, 1H).

Compound 1713-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-isopropylpropanamide

Following General Procedure H, B, the title compound was prepared from2-amino-4-chloro-benzenethiol, N-isopropyl-acrylamide, and4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.

¹H NMR (300 MHz, CD₃OD) δ 8.19 (d, J=1.47 Hz, 1H), 7.98 (d, J=8.20 Hz,1H), 7.60 (d, J=8.20 Hz, 1H), 7.23 (d, J=2.05 Hz, 1H), 7.06 (d, J=8.20Hz, 1H), 6.75 (dd, J=2.20, 8.35 Hz, 1H), 3.85-4.03 (m, 1H), 3.00 (t,J=7.33 Hz, 2H), 2.39 (t, J=7.47 Hz, 2H), 1.12 (d, 6H).

Compound 1723-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylpropanamide

Following General Procedure H, B, the title compound was prepared from2-amino-4-chloro-benzenethiol, N,N-dimethyl-acrylamide, and4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.

¹H NMR (300 MHz, CD₃OD) δ 8.11 (s, 1H), 7.90 (d, J=7.91 Hz, 1H),7.71-7.79 (m, 1H), 7.49 (d, J=2.34 Hz, 1H), 7.39 (d, J=8.50 Hz, 1H),7.21 (none, J=2.34, 8.50 Hz, 1H), 2.96 (d, J=7.62 Hz, 6H), 2.90 (t,J=7.03 Hz, 2H), 2.51 (t, J=7.03 Hz, 2H).

Compound 1733-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-isopropylpropanamide

Following General Procedure C, the title compound was prepared from3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylpropanamide

¹H NMR (300 MHz, CD₃OD) δ 8.17 (d, J=1.76 Hz, 1H), 8.01 (d, J=8.20 Hz,1H), 7.67 (d, J=8.50 Hz, 1H), 7.39 (d, J=8.20 Hz, 1H), 7.24 (d, J=1.76Hz, 1H), 6.88 (dd, J=1.90, 8.35 Hz, 1H), 3.91 (quin, J=6.59 Hz, 1H),3.37-3.52 (m, 1H), 3.09-3.25 (m, 1H), 2.58 (ddd, J=5.71, 9.89, 15.16 Hz,1H), 2.26 (ddd, J=5.86, 9.74, 15.16 Hz, 1H), 1.10 (dd, 4H).

Compound 1743-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propanamide

Following General Procedure H, B, the title compound was prepared from2-amino-4-chloro-benzenethiol, acrylamide, and4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.

¹H NMR (600 MHz, CD₃OD) δ 8.16 (d, J=1.76 Hz, 1H), 8.00 (dd, J=2.05,8.22 Hz, 1H), 7.75 (d, J=8.51 Hz, 1H), 7.57 (d, J=8.51 Hz, 1H), 7.32 (s,1H), 7.21 (d, J=7.92 Hz, 1H), 3.26 (br. s., 1H), 3.18 (br. s., 1H),2.99-3.07 (m, 3H), 2.95 (s, 3H), 2.88 (dt, J=7.37, 16.95 Hz, 1H),2.62-2.77 (m, 1H).

Compound 175 N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide

Following General Procedure B, C, the title compound was prepared from5-chloro-2-(methylsulfinyl)aniline and benzenesulfonyl chloride.

¹H NMR (300 MHz, acetone-d6) δ 10.64 (br. s., 1H), 7.93 (d, J=7.03 Hz,2H), 7.59-7.79 (m, 3H), 7.55 (d, J=1.76 Hz, 1H), 7.45 (d, J=8.50 Hz,1H), 7.26 (dd, J=1.90, 8.35 Hz, 1H), 2.74 (s, 3H).

Compound 176 N-[5-chloro-2-(methylthio)phenyl]thiophene-2-sulfonamide

Following General Procedure B, the title compound was prepared from5-chloro-2-(methylsulfinyl)aniline and thiophene-2-sulfonyl chloride.

¹H NMR (300 MHz, CD₃OD) 6 7.75 (dd, J=1.17, 4.98 Hz, 1H), 7.50 (dd,J=1.32, 3.66 Hz, 1H), 7.40 (d, J=2.05 Hz, 1H), 7.26-7.34 (m, 1H),7.15-7.24 (m, 1H), 7.08 (dd, J=3.81, 4.98 Hz, 1H), 2.23 (s, 3H).

Compound 177N-[5-chloro-2-(methylsulfinyl)phenyl]thiophene-2-sulfonamide

Following General Procedure C, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]thiophene-2-sulfonamide

¹H NMR (600 MHz, CD₃OD) δ 7.81 (d, J=4.40 Hz, 1H), 7.75 (d, J=8.51 Hz, 1H), 7.51-7.57 (m, 1H), 7.43 (d, J=7.92 Hz, 1H), 7.15 (dd, J=4.84, 8.66Hz, 2H), 2.79 (s, 3H).

Compound 178N-{2-[(3-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound (136mg, 82%) wasprepared from benzofuran-2-sulfonicacid[2-(3-nitro-benzylsulfanyl)-phenyl]-amide.

1H NMR (600 MHz, acetone-d6) δ 9.57 (br. s., 1H), 8.17 (dt, J=2.53, 6.38Hz, 1H), 7.93 (d, J=0.88 Hz, 1H), 7.74-7.83 (m, 3H), 7.69 (td, J=1.47,7.92 Hz, 1H), 7.63 (dd, J=1.47, 7.92 Hz, 1H), 7.52-7.59 (m, 3H), 7.47(ddd, J=1.17, 7.41, 8.44 Hz, 1H), 7.30-7.38 (m, 1H), 7.23 (t, J=7.63 Hz,1H), 4.85 (s, 2H).

Compound 179N-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (79mg, 73%) wasprepared fromN-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]thio}phenyl)-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.61 (d, J=7.92 Hz, 1H), 7.46 (d, J=2.05 Hz,1H), 7.44 (d, J=8.22 Hz, 1H), 7.28-7.32 (m, 1H), 7.21-7.26 (m, 1H), 7.19(dd, J=0.73, 8.36 Hz, 1H), 7.15 (d, J=0.88 Hz, 1H), 6.92 (dd, J=1.91,8.36 Hz, 1H), 3.52-3.62 (m, 1H), 2.80-2.91 (m, 2H), 2.56-2.65 (m, 1H),2.11 (s, 6H).

Compound 1804-chloro-N-{5-chloro-2-[(3-hydroxycyclopentyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure D, followed by treatment of the crudeproduct with NaBH₄ in MeOH, the title compound was prepared from4-Chloro-N-[5-chloro-2-(3-oxo-cyclopentylsulfanyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide(Intermediate 35).

1H NMR (600 MHz, CD₃OD) δ 8.34 (s, 1H), 8.18 (dd, J=1.91, 8.36 Hz, 1H),7.70-7.79 (m, 2H), 7.65 (s, 1H), 7.00 (br. s., 1H), 4.12-4.18 (m, 2H),1.98-2.10 (m, 2H), 1.72-1.84 (m, 2H), 1.63-1.71 (m, 2H).

Compound 181N-[5-chloro-2-(methylthio)phenyl]-4-methyl-3-nitrobenzenesulfonamide

Following General Procedure B, the title compound (197 mg, 61%) wasprepared from 5-Chloro-2-methylsulfanyl-phenylamine (150 mg, 0.87 mmol)and 4-Methyl-3-nitro-benzenesulfonyl chloride (235 mg, 0.87 mmol).

¹H NMR (600 MHz, CD₃OD) δ 8.29 (d, J=1.76 Hz, 1H), 7.85 (dd, J=1.91,8.07 Hz, 1H), 7.57 (d, J=8.22 Hz, 1H), 7.39 (d, J=2.05 Hz, 1H),7.17-7.25 (m, 2H), 2.60 (s, 3H), 2.20 (s, 3H).

Compound 182chloro-2-(methylsulfinyl)phenyl]-4-methyl-3-nitrobenzenesulfonamide

Following General Procedure C, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]-4-methyl-3-nitrobenzenesulfonamide

¹H NMR (600 MHz, CDCL₃) δ 10.88 (br. s., 1H), 8.53 (d, J=2.05 Hz, 1H),8.05 (dd, J=1.91, 8.07 Hz, 1H), 7.64 (d, J=1.76 Hz, 1H), 7.54 (d, J=8.22Hz, 1H), 7.04-7.16 (m, 2H), 2.87 (s, 3H), 2.67 (s, 3H).

Compound 183N-[5-chloro-2-(methylsulfonyl)phenyl]-4-methyl-3-nitrobenzenesulfonamide

Following General Procedure D, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]-4-methyl-3-nitrobenzenesulfonamide

¹H NMR (600 MHz, CDCL₃) δ 9.36 (br. s., 1H), 8.52 (d, J=2.05 Hz, 1H),8.05 (dd, J=2.05, 8.22 Hz, 1H), 7.79 (d, J=8.51 Hz, 1H), 7.67 (d, J=2.05Hz, 1H), 7.58 (d, J=7.92 Hz, 1H), 7.23 (dd, J=1.76, 8.51 Hz, 1H), 3.04(s, 3H), 2.68 (s, 3H).

Compound 1844-chloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide

Following General Procedure B, the title compound (150 mg, 68%) wasprepared from 5-Chloro-2-methylsulfanyl-phenylamine (110 mg, 0.64 mmol)and 4-Chloro-benzenesulfonyl chloride (134mg, 0.64 mmol).

¹H NMR (600 MHz, CD₃OD) δ 7.72 (d, J=9.10 Hz, 2H), 7.51 (d, J=8.80 Hz,2H), 7.37 (d, J=2.05 Hz, 1H), 7.25 (d, J=8.51 Hz, 1H), 7.19 (dd, J=2.05,8.22 Hz, 1H), 2.20 (s, 3H).

Compound 1854-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide

Following General Procedure C, the title compound was prepared from4-chloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide

¹H NMR (600 MHz, CDCL₃) δ 10.67 (br. s., 1H), 7.89 (d, J=8.80 Hz, 2H),7.66 (d, J=1.76 Hz, 1H), 7.50 (d, J=8.80 Hz, 2H), 6.91-7.16 (m, 2H),2.80 (none, 3H).

Compound 1864-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]benzenesulfonamide

Following General Procedure D, the title compound was prepared from4-chloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide

¹H NMR (600 MHz, CDCL₃) δ 7.89 (d, J=8.80 Hz, 2H), 7.78 (d, J=8.51 Hz,1H), 7.68 (d, J=1.76 Hz, 1H), 7.53 (d, J=8.80 Hz, 2H), 7.20 (dd, J=2.05,8.51 Hz, 1H), 2.96 (s, 3H).

Compound 1874-chloro-N-[5-chloro-2-(methylthio)phenyl]-3-methylbenzenesulfonamide

Following General Procedure B, the title compound (205 mg, 59%) wasprepared from 5-chloro-2-methylsulfanyl-phenylamine (165 mg, 0.95 mmol)and 4-chloro-3-methyl-benzenesulfonyl chloride (215mg, 0.95 mmol).

¹H NMR (600 MHz, CDCL₃) δ 7.71 (d, 1H), 7.65 (s, 1H), 7.62 (d, J=2.05Hz, 1H), 7.57 (dd, J=2.05, 8.22 Hz, 1H), 7.41 (d, J=8.22 Hz, 1H), 7.32(d, J=8.51 Hz, 1H), 7.04 (dd, J=2.20, 8.36 Hz, 1H), 2.39 (s, 3H), 2.19(s, 3H).

Compound 1884-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3-methylbenzenesulfonamide

Following General Procedure C, the title compound was prepared from4-chloro-N-[5-chloro-2-(methylthio)phenyl]-3-methylbenzenesulfonamide

¹H NMR (600 MHz, CDCL₃) δ 10.62 (s, 1H), 7.82 (d, J=2.05 Hz, 1H), 7.71(dd, J=1.91, 8.36 Hz, 1H), 7.63 (d, J=2.05 Hz, 1H), 7.48 (d, J=8.51 Hz,1H), 7.02-7.15 (m, 2H), 2.81 (s, 3H), 2.43 (s, 3H).

Compound 1894-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-3-methylbenzenesulfonamide

Following General Procedure D, the title compound was prepared from4-chloro-N-[5-chloro-2-(methylthio)phenyl]-3-methylbenzenesulfonamide

¹H NMR (600 MHz, CDCL₃) δ 9.24 (br. s., 1H), 7.83 (d, J=2.05 Hz, 1H),7.78 (d, J=8.51 Hz, 1H), 7.71 (dd, J=2.05, 8.51 Hz, 1H), 7.67 (d, J=1.76Hz, 1H), 7.50 (d, J=8.22 Hz, 1H), 7.19 (dd, J=1.76, 8.51 Hz, 1H), 2.97(s, 3H), 2.44 (s, 3H).

Compound 190N-[5-chloro-2-(methylthio)phenyl]-3-nitro-4-(trifluoromethyl)benzenesulfonamide

Following General Procedure B, the title compound (176 mg, 43%) wasprepared from 5-chloro-2-methylsulfanyl-phenylamine (167 mg, 0.95 mmol)and 4-nitro-3-trifluoromethyl-benzenesulfonyl chloride (278mg, 0.95mmol).

¹H NMR (300 MHz, CD₃OD) δ 8.04-8.22 (m, 3H), 7.42 (d, J=2.05 Hz, 1H),7.16-7.32 (m, 2H), 2.20 (s, 3H).

Compound 191N-[5-chloro-2-(methylsulfonyl)phenyl]-3-nitro-4-(trifluoromethyl)benzenesulfonamide

Following General Procedure D, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]-3-nitro-4-(trifluoromethyl)benzenesulfonamide

¹H NMR (600 MHz, acetone-d6) δ 9.64 (br. s., 1H), 8.49-8.65 (m, 2H),8.33 (d, J=8.51 Hz, 1H), 7.89 (d, J=8.51 Hz, 1H), 7.70 (d, J=1.76 Hz,1H), 7.39 (d, J=8.22 Hz, 1H), 3.24 (s, 3H).

Compound 192N-[5-chloro-2-(methylsulfinyl)phenyl]-3-nitro-4-(trifluoromethyl)benzenesulfonamide

Following General Procedure D, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]-3-nitro-4-(trifluoromethyl)benzenesulfonamide

¹H NMR (600 MHz, acetone-d6) δ 8.25-8.35 (m, 2H), 8.11 (d, J=8.22 Hz,1H), 7.39-7.48 (m, 2H), 6.75 (dd, J=2.05, 8.22 Hz, 1H), 2.70 (s, 3H).

Compound 193N-[5-chloro-2-(methylthio)phenyl]-2,4-difluorobenzenesulfonamide

Following General Procedure B, the title compound (358 mg, 94%) wasprepared from 5-chloro-2-methylsulfanyl-phenylamine (189 mg, 1.09 mmol)and 2,4-Difluoro-benzenesulfonyl chloride (231mg, 1.09 mmol).

¹H NMR (300 MHz, CD₃OD) δ 7.82 (td, J=6.15, 8.50 Hz, 1H), 7.34 (d,J=2.05 Hz, 1H), 7.16-7.30 (m, 3H), 7.00-7.16 (m, 1H), 2.27 (s, 3H).

Compound 194N-[5-chloro-2-(methylsulfonyl)phenyl]-2,4-difluorobenzenesulfonamide

Following General Procedure D, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]-2,4-difluorobenzenesulfonamide

¹H NMR (300 MHz, acetone-d6) δ 9.81 (br. s., 1H), 8.15-8.32 (m, 1H),7.91 (d, J=8.50 Hz, 1H), 7.63 (d, J=1.76 Hz, 1H), 7.24-7.46 (m, 3H),3.27 (s, 3H).

Compound 195N-[5-chloro-2-(methylsulfinyl)phenyl]-2,4-difluorobenzenesulfonamide

Following General Procedure D, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]-2,4-difluorobenzenesulfonamide

¹H NMR (600 MHz, acetone-d6) δ 10.97 (br. s., 1H), 8.10 (td, J=6.16,8.51 Hz, 1H), 7.51 (d, J=8.22 Hz, 1H), 7.46 (d, J=2.05 Hz, 1H),7.30-7.38 (m, 1H), 7.24-7.31 (m, 2H), 2.90 (s, 3H).

Compound 196N-[5-chloro-2-(methylthio)phenyl]-5-methylfuran-2-sulfonamide

Following General Procedure B, the title compound (212 mg, 48%) wasprepared from 5-chloro-2-methylsulfanyl-phenylamine (189 mg, 1.09 mmol)and 5-methyl-furan-2-sulfonyl chloride (250mg, 1.38 mmol).

¹H NMR (300 MHz, acetone-d6) δ 8.53 (br. s., 1H), 7.37-7.49 (m, 2H),7.25 (dd, J=2.34, 8.50 Hz, 1H), 6.96 (d, J=3.22 Hz, 1H), 6.24 (d, J=2.64Hz, 1H), 2.38 (s, 3H), 2.34 (s, 3H).

Compound 197N-[5-chloro-2-(methylsulfinyl)phenyl]-5-methylfuran-2-sulfonamide

Following General Procedure C, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]-5-methylfuran-2-sulfonamide

¹H NMR (600 MHz, acetone-d6) δ 10.74 (br. s., 1H), 7.55 (d, J=2.05 Hz,1H), 7.51 (d, J=8.22 Hz, 1H), 7.30 (dd, J=1.91, 8.36 Hz, 1H), 7.18 (d,J=3.23 Hz, 1H), 6.24-6.35 (m, 1H), 2.90 (s, 3H), 2.34 (s, 3H).

Compound 198N-[5-chloro-2-(methylsulfonyl)phenyl]-5-methylfuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]-5-methylfuran-2-sulfonamide

¹H NMR (600 MHz, acetone-d6) δ 9.54 (br. s., 1H), 7.90 (d, J=8.51 Hz,1H), 7.73 (d, J=2.05 Hz, 1H), 7.39 (dd, J=1.76, 8.51 Hz, 1H), 7.31 (d,J=3.52 Hz, 1H), 6.32 (d, J=3.23 Hz, 1H), 3.24 (s, 3H), 2.33 (s, 3H).

Compound 199 N-[5-chloro-2-(methylthio)phenyl]furan-2-sulfonamide

Following General Procedure B, the title compound (215 mg, 47%) wasprepared from 5-chloro-2-methylsulfanyl-phenylamine (260 mg, 1.50 mmol)and furan-2-sulfonyl chloride (250mg, 1.50 mmol).

¹H NMR (300 MHz, acetone-d6) δ 8.67 (br. s., 1H), 7.84 (s, 1H),7.32-7.46 (m, 2H), 7.26 (dd, J=2.20, 8.35 Hz, 1H), 7.07 (d, J=3.52 Hz,1H), 6.63 (dd, J=1.76, 3.52 Hz, 1H), 2.36 (s, 3H).

Compound 200 N-[5-chloro-2-(methylsulfinyl)phenyl]furan-2-sulfonamide

Following General Procedure C, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]furan-2-sulfonamide

¹H NMR (600 MHz, acetone-d6) δ 10.85 (br. s., 1H), 7.89 (s, 1H),7.49-7.59 (m, 2H), 7.28-7.36 (m, 2H), 6.68 (dd, J=1.76, 3.52 Hz, 1H),2.88 (s, 3H).

Compound 201 N-[5-chloro-2-(methylsulfonyl)phenyl]furan-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-[5-chloro-2-(methylthio)phenyl]furan-2-sulfonamide

¹H NMR (600 MHz, acetone-d6) δ 9.62 (br. s., 1H), 7.90 (d, J=8.51 Hz,2H), 7.74 (d, J=2.05 Hz, 1H), 7.27-7.48 (m, 2H), 6.70 (dd, J=1.76, 3.52Hz, 1H), 3.22 (s, 3H).

Compound 2024-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide

Following General Procedure B, the title compound (380 mg, 66%) wasprepared from 5-chloro-2-methylsulfanyl-phenylamine (273 mg, 1.57 mmol)and 4-chloro-2-fluoro-benzenesulfonyl chloride (360mg, 1.57 mmol).

¹H NMR (300 MHz, acetone-d6) δ 8.77 (br. s., 1H), 7.84 (t, J=8.06 Hz,1H), 7.53 (dd, J=1.90, 9.82 Hz, 1H), 7.35-7.48 (m, 3H), 7.25 (dd,J=2.20, 8.35 Hz, 1H), 2.34 (s, 3H).

Compound 2034-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-2-fluorobenzenesulfonamide

Following General Procedure C, the title compound was prepared from4-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide

¹H NMR (300 MHz, acetone-d6) δ 10.95 (br. s., 1H), 8.03 (t, J=8.20 Hz,1H), 7.39-7.61 (m, 4H), 7.28 (dd, J=1.90, 8.35 Hz, 1H), 2.93 (s, 3H).

Compound 2044-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-2-fluorobenzenesulfonamide

Following General Procedure D, the title compound was prepared from4-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide

¹H NMR (300 MHz, acetone-d6) δ 9.84 (br. s., 1H), 8.12 (t, J=8.20 Hz,1H), 7.90 (d, J=8.50 Hz, 1H), 7.46-7.69 (m, 3H), 7.33 (dd, J=1.47, 8.50Hz, 1H), 3.27 (s, 3H).

Compound 2053-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide

Following General Procedure B, the title compound (386 mg, 62%) wasprepared from 5-chloro-2-methylsulfanyl-phenylamine (297 mg, 1.71 mmol)and 3-chloro-2-fluoro-benzenesulfonyl chloride (392mg, 1.71 mmol).

¹H NMR (300 MHz, acetone-d6) δ 8.87 (br. s., 1H), 7.70-7.93 (m, 2H),7.32-7.47 (m, 3H), 7.20-7.31 (m, 1H), 2.32 (s, 3H).

Compound 2063-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-2-fluorobenzenesulfonamide

Following General Procedure D, the title compound was prepared from3-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide

¹H NMR (300 MHz, acetone-d6) δ 7.89-8.04 (m, 1H), 7.69 (d, J=8.50 Hz,1H), 7.55-7.65 (m, 2H), 7.23-7.37 (m, 1H), 6.72 (dd, J=1.90, 8.64 Hz,1H), 3.22 (s, 3H).

Compound 2073-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-2-fluorobenzenesulfonamide

Following General Procedure C, the title compound was prepared from3-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide

¹H NMR (300 MHz, acetone-d6) δ 7.94-8.04 (m, 1H), 7.83-7.93 (m, 1H),7.42-7.59 (m, 3H), 7.29 (dd, J=1.90, 8.35 Hz, 1H), 2.93 (s, 3H).

Compound 2084-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure A, B, the title compound was prepared from2-Amino-4-chloro-benzenethiol, 2-chloromethyl-1H-imidazole and4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.

¹H NMR (300 MHz, CD₃OD) δ 8.06 (d, J=1.76 Hz, 1H), 7.89 (dd, J=2.05,8.50 Hz, 1H), 7.63-7.78 (m, 2H), 7.45 (d, J=2.05 Hz, 1H), 7.30 (d,J=8.50 Hz, 1H), 7.14 (dd, J=2.34, 8.50 Hz, 1H), 6.73 (s, 1H), 3.83 (s,2H).

Compound 2094-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure C, the title compound was prepared from4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide.

¹H NMR (600 MHz, CD₃OD) δ 8.18 (d, 1H), 8.03 (dd, J=1.91, 8.36 Hz, 1H),7.72 (d, J=8.22 Hz, 1H), 7.41 (s, 2H), 7.20 (d, J=1.76 Hz, 1H), 7.06 (d,J=8.51 Hz, 1H), 6.84 (dd, J=1.91, 8.36 Hz, 1H), 4.76 (d, J=8.22 Hz, 2H).

Compound 2104-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide

¹H NMR (600 MHz, acetone-d6) δ 8.33 (d, J=1.76 Hz, 1H), 8.18 (dd,J=1.76, 8.22 Hz, 1H), 7.70 (d, J=8.22 Hz, 1H), 7.66 (d, J=8.51 Hz, 1H),7.58 (d, J=2.05 Hz, 1H), 7.10 (s, 2H), 6.72 (dd, J=1.91, 8.36 Hz, 1H),4.86 (s, 2H).

Compound 2114-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure A, B, the title compound was prepared from2-Amino-4-chloro-benzenethiol, 4-chloromethyl-1H-imidazole hydrogenchloride and 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.

¹H NMR (600 MHz, acetone-d6) δ 8.07 (d, J=2.05 Hz, 1H), 7.89-7.97 (m,2H), 7.77 (d, J=8.51 Hz, 1H), 7.61 (d, J=2.35 Hz, 1H), 7.56 (d, J=8.22Hz, 1H), 7.16 (dd, J=2.35, 8.22 Hz, 1H), 7.02 (s, 1H), 3.87 (s, 2H).

Compound 2124-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Following General Procedure C, the title compound was prepared from4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide.

¹H NMR (600 MHz, acetone-d6) δ 8.26 (br. s., 1H), 8.17 (s, 1H), 8.08(dd, J=1.76, 8.51 Hz, 1H), 7.82 (d, J=8.51 Hz, 1H), 7.47 (br. s., 1H),7.38 (d, J=8.51 Hz, 1H), 7.30 (s, 1H), 7.09 (d, J=7.92 Hz, 1H), 4.48(dd, J=2.35, 13.79 Hz, 1H), 4.20 (d, J=14.09 Hz, 1H).

Compound 213N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure A, B, the title compound was prepared from2-Amino-4-chloro-benzenethiol, 2-chloromethyl-1H-imidazole and1-benzofuran-2-sulfonyl chloride.

¹H NMR (600 MHz, acetone-d6) δ 7.74 (d, J=7.92 Hz, 1H), 7.64 (d, J=2.35Hz, 1H), 7.61 (d, J=8.51 Hz, 1H), 7.53 (d, J=8.51 Hz, 1H), 7.46 (td,J=1.17, 7.78 Hz, 1H), 7.41 (s, 1H), 7.33 (t, J=7.48 Hz, 1H), 7.17 (s,2H), 7.09 (dd, J=2.35, 8.22 Hz, 1H), 4.10 (s, 2H).

Compound 214N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound was prepared fromN-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

¹H NMR (300 MHz, DMSO-d6) δ 7.68 (d, J=7.62 Hz, 1H), 7.51-7.61 (m, 3H),7.41 (d, J=2.05 Hz, 1H), 7.32-7.40 (m, 1H), 7.21-7.32 (m, 1H), 7.17 (s,1H), 6.92 (d, J=8.50 Hz, 1H), 6.74 (dd, J=1.90, 8.06 Hz, 1H), 4.89 (d,J=14.07 Hz, 1H), 4.56 (d, J=13.77 Hz, 1H).

Compound 215N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

¹H NMR (300 MHz, acetone-d6) δ 7.69-7.79 (m, 3H), 7.66 (s, 2H),7.46-7.54 (m, 1H), 7.41 (s, 2H), 7.24-7.34 (m, 1H), 6.88 (dd, J=1.90,8.64 Hz, 1H), 5.62 (s, 2H).

Compound 216N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound was prepared fromN-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.

¹H NMR (300 MHz, acetone-d6) δ 8.34 (s, 1H), 7.75 (d, J=7.91 Hz, 1H),7.60 (d, J=2.05 Hz, 1H), 7.47-7.56 (m, 2H), 7.43 (t, J=7.33 Hz, 1H),7.24-7.38 (m, 3H), 7.03 (d, J=10.55 Hz, 1H), 4.58 (d, J=14.36 Hz, 1H),4.24 (d, J=13.77 Hz, 1H)

Compound 217N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide

¹H NMR (300 MHz, acetone-d6) δ 8.20 (br. s., 1H), 7.66-7.81 (m, 3H),7.35-7.53 (m, 4H), 7.23-7.35 (m, 1H), 6.95 (dd, J=2.05, 8.50 Hz, 1H),4.87 (s, 2H).

Compound 218N-[2-({2-[(aminocarbonyl)amino]ethyl}thio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide

Following General Procedure A, B, the title compound was prepared from2-Amino-4-chloro-benzenethiol, (2-chloro-ethyl)-urea and1-benzofuran-2-sulfonyl chloride.

1H NMR (300 MHz, acetone-d6) δ 7.77 (d, J=7.91 Hz, 1H), 7.45-7.66 (m,5H), 7.31-7.42 (m, 1H), 7.22 (dd, J=2.05, 8.50 Hz, 1H), 6.02 (br. s.,1H), 5.40 (br. s., 2H), 3.14 (q, J=6.15 Hz, 2H), 2.84 (t, J=6.45 Hz,2H).

Compound 219N-[2-({2-[(aminocarbonyl)amino]ethyl}sulfinyl)-5-chlorophenyl]-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound was prepared fromN-[2-({2-[(aminocarbonyl)amino]ethyl}thio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide

¹H NMR (600 MHz, CD₃OD) δ 7.68 (d, J=7.92 Hz, 1H), 7.54 (dd, J=5.28,8.22 Hz, 2H), 7.42 (t, J=7.92 Hz, 1H), 7.37 (s, 1H), 7.27-7.34 (m, 2H),7.10 (d, J=6.75 Hz, 1H), 3.58-3.67 (m, 1H), 3.44-3.53 (m, 1H), 3.36-3.43(m, 1H), 2.98-3.09 (m, 1H).

Compound 220N-[2-({2-[(aminocarbonyl)amino]ethyl}sulfonyl)-5-chlorophenyl]-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-[2-({2-[(aminocarbonyl)amino]ethyl}thio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, CD₃OD) δ 7.85 (d, J=8.51 Hz, 1H), 7.80 (d, J=2.05 Hz,1H), 7.77 (d, J=7.92 Hz, 1H), 7.72 (s, 1H), 7.61 (d, J=8.51 Hz, 1H),7.52 (t, J=7.34 Hz, 1H), 7.31-7.40 (m, 2H), 3.36-3.47 (m, 4H).

Compound 221N-(5-chloro-2-{[3-(dimethylamino)propyl]thio}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure A, B, the title compound was prepared from2-Amino-4-chloro-benzenethiol, (3-chloro-propyl)-dimethyl-aminehydrochloride and 1-benzofuran-2-sulfonyl chloride.

¹H NMR (600 MHz, acetone-d6) δ 7.62-7.72 (m, 2H), 7.49 (d, J=8.22 Hz,1H), 7.31-7.38 (m, 2H), 7.25 (t, J=7.48 Hz, 1H), 7.18 (s, 1H), 6.69 (dd,J=2.05, 8.22 Hz, 1H), 3.44 (t, J=5.58 Hz, 2H), 3.30 (s, 3H), 3.12 (s,3H), 2.97 (t, J=6.31 Hz, 2H), 1.96-2.10 (m, 2H)

Compound 222N-(5-chloro-2-{[3-(dimethylamino)propyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound was prepared fromN-(5-chloro-2-{[3-(dimethylamino)propyl]thio}phenyl)-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, acetone-d6) δ 7.67 (d, J=7.92 Hz, 1H), 7.60 (d, J=1.76Hz, 1H), 7.50 (d, J=8.22 Hz, 1H), 7.41 (d, J=8.22 Hz, 1H), 7.33 (t,J=7.92 Hz, 1H), 7.20-7.28 (m, 2H), 6.83 (dd, J=1.76, 8.22 Hz, 1H), 3.69(ddd, J=4.99, 8.58, 13.43 Hz, 1H), 3.61 (ddd, J=4.11, 10.71, 14.23 Hz,1H), 3.48 (ddd, J=5.58, 5.72, 13.35 Hz, 1H), 3.07-3.21 (m, 7H),2.30-2.42 (m, 1H), 2.16-2.30 (m, 1H).

Compound 223N-(5-chloro-2-{[3-(dimethylamino)propyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-(5-chloro-2-{[3-(dimethylamino)propyl]thio}phenyl)-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, acetone-d6) δ 7.63 (d, J=7.63 Hz, 1H), 7.53 (d, J=1.76Hz, 1H), 7.48 (d, J=8.22 Hz, 1H), 7.43 (d, J=8.22 Hz, 1H), 7.30 (t,J=7.34 Hz, 1H), 7.21 (t, J=7.21 Hz, 1H), 7.17 (s, 1H), 6.74 (dd, J=2.05,8.22 Hz, 1H), 3.60-3.69 (m, 2H), 3.36-3.48 (m, 1H), 3.20-3.33 (m, 6H),2.90-3.01 (br. s., 1H), 2.29-2.42 (m, J=6.75 Hz, 1H), 2.08-2.21 (m, 1H).

Compound 224N-(5-chloro-2-{[3-(dimethylnitroryl)propyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-(5-chloro-2-{[3-(dimethylamino)propyl]thio}phenyl)-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, acetone-d6) d 7.79 (s, 1H), 7.70 (d, J=8.51 Hz, 1H),7.64 (d, J=7.63 Hz, 1H), 7.52 (d, J=8.51 Hz, 1H), 7.29-7.38 (m, 2H),7.19-7.28 (m, 1H), 6.74 (d, J=8.51 Hz, 1H), 3.74-3.84 (m, 2H), 3.60-3.65(m., 2H), 3.26 (s, 6H), 2.27-2.39(m, 2H).

Compound 225N-(5-chloro-2-{[(2-oxo-1,3-oxazolidin-5-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure A, B, C, the title compound was preparedfrom 2-Amino-4-chloro-benzenethiol, 5-chloromethyl-oxazolidin-2-one and1-benzofuran-2-sulfonyl chloride.

¹H NMR (600 MHz, acetone-d6) δ 7.62 (dd, J=7.92, 11.15 Hz, 1H),7.44-7.54 (m, 2H), 7.26-7.44 (m, 3H), 7.20 (ddd, J=7.48, 7.63, 11.30 Hz,1H), 6.87-7.05 (m, 1H), 6.51 (br. s., 1H), 4.69-5.03 (m, 1H), 3.60 (q,J=8.31 Hz, 1H), 3.45-3.55 (m, 1H), 3.23-3.45 (m, 1H), 3.06-3.17 (m, 1H).

Compound 226N-(5-chloro-2-{[(2-oxo-1,3-oxazolidin-5-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-(5-chloro-2-{[(2-oxo-1,3-oxazolidin-5-yl)methyl]thio)phenyl)benzofuran-2-sulfonamide.

¹H NMR (600 MHz, acetone-d6) δ 7.81 (d, J=1.76 Hz, 1H), 7.68 (d, J=8.22Hz, 2H), 7.54 (d, J=8.22 Hz, 1H), 7.29-7.40 (m, 2H), 7.22-7.29 (m, 1H),6.79 (br. s., 1H), 6.47 (br. s., 1H), 4.94 (dt, J=6.93, 14.01 Hz, 1H),4.17 (dd, J=5.58, 14.09 Hz, 1H), 3.96 (dd, J=6.90, 14.23 Hz, 1H), 3.65(t, J=8.66 Hz, 1H), 3.32-3.47 (m, 1H).

Compound 227N-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedures A and B the title compound was preparedfrom 2-amino-4-chloro-benzenethiol,6-chloromethyl-1H-pyrimidine-2,4-dione and 1-benzofuran-2-sulfonylchloride.

¹H NMR (600 MHz, CD₃OD) δ 7.72 (d, J=7.92 Hz, 1H), 7.57 (d, J=8.22 Hz,1H), 7.45-7.51 (m, 1H), 7.44 (d, J=2.05 Hz, 1H), 7.42 (s, 1H), 7.27-7.37(m, 2H), 7.09 (br. s., 1H), 5.05 (s, 1H), 3.64 (s, 2H).

Compound 228N-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound was prepared fromN-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, CD₃OD) δ 7.68 (d, J=7.92 Hz, 1H), 7.52 (d, J=8.51 Hz,1H), 7.49 (d, J=8.51 Hz, 1H), 7.41 (t, J=7.92 Hz, 1H), 7.32-7.37 (m,2H), 7.27-7.32 (m, 1H), 7.09 (d, J=8.22 Hz, 1H), 5.32 (s, 1H), 4.40 (d,J=13.21 Hz,1H), 3.89 (d, J=12.91 Hz, 1H).

Compound 229N-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound was prepared fromN-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.

¹H NMR (600 MHz, acetone-d6) δ 10.36 (br. s., 1H), 10.15 (br. s., 1H),7.78 (br. s., 1H), 7.70 (d, J=8.51 Hz, 1H), 7.65 (d, J=7.92 Hz, 1H),7.42-7.51 (m, 2H), 7.35 (t, J=7.63 Hz, 1H), 7.26 (t, J=7.48 Hz, 1H),6.87 (d, J=6.75 Hz, 1H), 5.48 (br. s., 1H), 4.76 (br. s., 2H).

Compound 230N-{2-[(3-aminopropyl)thio]-5-chlorophenyl}-1-benzofuran-2-sulfonamide

Following General Procedure F, G, the title compound was prepared from2,2′-dithiobis(5-chloroaniline), 1-benzofuran-2-sulfonyl chloride and3-bromo-propylamine hydrochloride.

¹H NMR (600 MHz, DMSO-d6) δ 8.03 (br. s., 2H), 7.69 (d, J=7.63 Hz, 1H),7.56 (d, J=8.22 Hz, 1H), 7.37 (t, J=7.78 Hz, 1H), 7.23-7.32 (m, 2H),7.05-7.20 (m, 2H), 6.60 (br. s., 1H), 3.03 (br. s., 2H), 2.91 (t, J=6.60Hz, 2H), 1.74-1.92 (m, 2H).

Intermediate 38 (3-Bromo-propyl)-carbamic acid tert-butyl ester

A mixture of 3-bromo-propylamine hydrochloride (523 mg, 2.39 mmol),di-tert-butyl dicarbonate (573 mg, 2.63 mmol), NaOH (1N, 1.5 ml) in MeOHwas stirred at rt overnight. The mixture was added water and extractedwith EtOAc. The organic layer was washed with brine, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by columnchromatography in silica gel.

¹H NMR (600 MHz, CDCl₃) δ 4.65 (br. s., 1H), 3.38-3.56 (m, 2H), 3.28 (d,J=5.28 Hz, 2H), 1.95-2.14 (m, 2H), 1.45 (br. s., 9H).

Compound 231N-{2-[(3-aminopropyl)sulfinyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide

Following General Procedure F, G, C, E the title compound was preparedfrom 2,2′-dithiobis(5-chloroaniline), 1-benzofuran-2-sulfonyl chlorideand (3-bromo-propyl)-carbamic acid tert-butyl ester.

¹H NMR (600 MHz, acetone-d6) δ 7.78 (d, J=7.92 Hz, 1H), 7.63 (d, J=8.51Hz, 1H), 7.54-7.59 (m, 2H), 7.46-7.52 (m, 2H), 7.32-7.40 (m, 1H), 7.21(d, J=7.92 Hz, 1H), 4.03-4.14 (m, 1H), 3.88-4.00 (m, 1H), 3.35 (ddd,J=6.97, 7.19, 13.72 Hz, 1H), 3.10 (ddd, J=6.46, 6.60, 13.35 Hz, 1H),2.16-2.36 (m, 2H).

Compound 232N-{2-[(3-aminopropyl)sulfonyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide

Following General Procedure F, G, D, E the title compound was preparedfrom 2,2′-dithiobis(5-chloroaniline), 1-benzofuran-2-sulfonyl chlorideand (3-bromo-propyl)-carbamic acid tert-butyl ester.

¹H NMR (600 MHz, CD₃OD) δ 7.88 (d, J=8.51 Hz, 1H), 7.79 (d, J=7.92 Hz,1H), 7.72 (d, J=1.76 Hz, 1H), 7.68 (s, 1H), 7.61 (d, J=8.51 Hz, 1H),7.53 (t, J=7.78 Hz, 1H), 7.40 (t, J=7.63 Hz, 1H), 7.34 (d, J=8.51 Hz,1H), 3.47 (t, J=7.04 Hz, 2H), 3.02 (t, J=7.63 Hz, 2H), 2.06 (quin, 2H).

Compound 233N-(5-chloro-2-{[(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure A, B, C, the title compound was preparedfrom 2-amino-4-chloro-benzenethiol, 5-(chloromethyl)uracil and1-benzofuran-2-sulfonyl chloride.

¹H NMR (600 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.75 (br. s., 1H), 7.61 (d,J=7.63 Hz, 1H), 7.51 (d, J=8.22 Hz, 1H), 7.32 (t, J=7.48 Hz, 1H),7.16-7.27 (m, 3H), 7.01-7.10 (m, 1H), 6.86 (br. s., 1H), 6.64-6.79 (m,1H), 4.02 (d, J=13.21 Hz, 1H), 3.85 (d, J=13.21 Hz, 1H).

Compound 234N-(5-chloro-2-{[(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure A, B, D, the title compound was preparedfrom 2-amino-4-chloro-benzenethiol, 5-(chloromethyl)uracil and1-benzofuran-2-sulfonyl chloride.

¹H NMR (600 MHz, CD₃OD) δ 7.69 (d, J=2.05 Hz, 1H), 7.63-7.67 (m, 2H),7.44 (t, J=8.36 Hz, 1H), 7.32-7.39 (m, 2H), 7.27 (t, J=7.04 Hz, 1H),7.18 (s, 1H), 6.82 (d, J=7.92 Hz, 1H), 4.70 (s, 2H).

Compound 235N-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}acetamide

Following General Procedure A, B, the title compound was prepared from2-amino-4-chloro-benzenethiol, N-(4-Chloromethyl-thiazol-2-yl)-acetamideand 1-benzofuran-2-sulfonyl chloride.

1H NMR (600 MHz, CD₃OD) d 7.70 (d, J=7.92 Hz, 1H), 7.49-7.54 (m, 2H),7.45-7.50 (m, 1H), 7.42 (s, 1H), 7.29-7.36 (m, 2H), 7.11 (dd, J=2.20,8.36 Hz, 1H), 6.45 (s, 1H), 3.84 (s, 2H), 2.21 (s, 3H).

Compound 236N-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]-1,3-thiazol-2-yl}acetamide

Following General Procedure C, the title compound was prepared fromN-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}acetamide.

¹H NMR (600 MHz, acetone-d6) δ 10.93 (br. s., 1H), 7.83 (d, J=7.92 Hz,1H), 7.80 (s, 1H), 7.62-7.67 (m, 2H), 7.49-7.58 (m, 1H), 7.39 (t, J=7.48Hz, 1H), 7.08-7.22 (m, 2H), 6.74 (s, 1H), 4.29-4.46 (m, 2H), 2.23 (s,3H).

Compound 237N-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]-1,3-thiazol-2-yl}acetamide

Following General Procedure D, the title compound was prepared fromN-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}acetamide.

1H NMR (600 MHz, acetone-d6) δ 10.90 (br. s., 1H), 9.65 (br. s., 1H),7.81 (d, J=7.34 Hz, 2H), 7.75 (d, J=2.05 Hz, 1H), 7.65 (d, J=8.51 Hz,1H), 7.60 (s., 1H), 7.51 (s., 1H), 7.38 (t, J=7.19 Hz, 1H), 7.27 (s.,1H), 6.95 (s, 1H), 4.67 (br. s., 2H), 2.21 (s, 3H).

Compound 238N-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide

Following General Procedure D, the title compound (53mg, 38%) wasprepared fromN-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]thio}phenyl)-1-benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.79 (d, J=1.76 Hz, 1H), 7.76 (d, J=8.51 Hz,1H), 7.67 (d, J=7.92 Hz, 1H), 7.57 (d, J=0.59 Hz, 1H), 7.37 (ddd,J=1.17, 7.19, 8.36 Hz, 1H), 7.26-7.31 (m, 1H), 7.20-7.24 (m, 1H), 7.15(dd, J=1.76, 8.51 Hz, 1H), 3.40-3.50 (m, 2H), 2.60-2.72 (m, 2H), 2.01(s, 6H).

Compound 239N-{5-fluoro-2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure C, the title compound (174mg, 79%) wasprepared fromN-(5-fluoro-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.

1H NMR (600 MHz, CD₃OD) δ 7.98 (d, J=9.10 Hz, 1H), 7.67 (d, J=7.63 Hz,1H), 7.49 (br. s., 1H), 7.40 (s, 1H), 7.35 (d, J=8.51 Hz, 1H), 7.26-7.32(m, 2H), 7.21-7.26 (m, 2H), 7.12 (d, J=7.63 Hz, 1H), 6.74-6.80 (m, 1H),6.40 (t, J=7.34 Hz, 1H), 4.52-4.64 (m, 2H).

Compound 240N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-2,4-difluorobenzenesulfonamide

Following General Procedure A, B, C, and K, the title compound wasprepared from 2-amino-4-chloro-benzenethiol,1-bromomethyl-3-nitro-benzene, and 2,4-difluoro-benzenesulfonylchloride.

¹H NMR (600 MHz, METHANOL-d₄) δ 7.95 (d, J=6.16 Hz, 1H), 7.19-7.30 (m,3H), 7.11-7.19 (m, 2H), 7.00 (t, J=7.78 Hz, 1H), 6.72 (dd, J=1.47, 7.92Hz, 1H), 6.61 (s, 1H), 6.44 (d, J=7.04 Hz, 1H), 4.34 (d, J=12.91 Hz,1H), 4.07 (d, J=12.90 Hz, 1H).

Compound 241N-[5-chloro-2-(methylsulfonyl)phenyl]-4-isopropylbenzenesulfonamide

Following General Procedure B and D, the title compound was preparedfrom 5-chloro-2-(methylthio)aniline and 4-isopropyl-benzenesulfonylchloride.

¹H NMR (600 MHz, CHLOROFORM-d) δ 9.13 (s, 1H), 7.80-7.85 (m, 2H),7.71-7.76 (m, 2H), 7.34-7.39 (m, 2H), 7.16 (dd, J=2.05, 8.51 Hz, 1H),2.95 (spt, J=6.90 Hz, 1H), 2.81 (s, 3H), 1.22 (d, J=7.04 Hz, 6H).

Compound 242N-(5-methoxy-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide

Following General Procedure B, the title compound (406 mg, 56%) wasprepared from 5-methoxy-2-((3-nitrobenzyl)thio)aniline (450 mg, 1.552mmol) and benzofuran-2-sulfonyl chloride (335 mg, 1.552 mmol)in pyridine(5 ml).

1H NMR (600 MHz, CD₃OD) δ 8.53 (dd, J=1.76, 5.87 Hz, 1H), 7.96 (ddd,J=1.03, 2.27, 8.14 Hz, 1H), 7.70 (d, J=7.92 Hz, 1H), 7.63 (t, J=1.91 Hz,1H), 7.51 (s, 1H), 7.42 (dd, J=1.17, 8.22 Hz, 1H), 7.24-7.37 (m, 3H),7.11 (s, 1H), 7.00 (s, 1H), 6.55 (dd, J=2.79, 8.66 Hz, 1H), 3.83 (s,2H), 3.71 (s, 3H).

Compound 243N-{5-chloro-2-[(1H-pyrazol-3-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide

Following General Procedure D and E, the title compound was preparedfrom tert-butyl3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1H-pyrazole-1-carboxylate(Compound 22).

¹H NMR (600 MHz, CD₃OD) δ 7.71 (d, J=1.76 Hz, 1H), 7.66 (d, J=7.92 Hz,1H), 7.51 (d, J=8.51 Hz, 1H), 7.31-7.43 (m, 4H), 7.24-7.29 (m, 1H), 6.79(d, J=7.04 Hz, 1H), 5.82 (br. s., 1H), 4.99 (br. s., 2H).

Compound 244N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-4-chloro-2-fluorobenzenesulfonamide

Following General Procedure A, B, and K, the title compound was preparedfrom 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and4-chloro-2-fluoro-benzenesulfonyl chloride.

¹H NMR (600 MHz, CHLOROFORM-d) δ 7.84 (t, J=8.22 Hz, 1H), 7.47 (d,J=2.05 Hz, 1H), 7.25 (dt, J=1.03, 8.51 Hz, 1H), 7.17-7.22 (m, 2H), 7.04(t, J=7.63 Hz, 1H), 6.93 (dd, J=2.35, 8.22 Hz, 1H), 6.58 (dt, J=1.17,7.92 Hz, 1H), 6.40-6.45 (m, 2H), 3.72 (s, 2H).

Biological Data

HEK-Gqi5 cells stably expressing CCR2 were cultured in (DMEM highglucose, 10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/ml hygromycin.Appropriate positive control chemokines (MCP-1, MIP1A or RANTES) wasused as the positive control agonist for screening compound-inducedcalcium activity assayed on the FLIPR^(Tetra). The drug plates wereprepared in 384-well microplates using the EP3 and the MuItiPROBErobotic liquid handling systems. Compounds were synthesized and testedfor CCR2 activity.

Table 1 shows activity at CCR2 receptor (IC₅₀) nM

TABLE 1 CCR2 CCR2% Compound Name IC₅₀ (nM) ANTAGONISM4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3- 14 78(trifluoromethyl)benzenesulfonamide4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-3- 64 90(trifluoromethyl)benzenesulfonamide4-chloro-N-[5-chloro-2-(methylthio)phenyl]-3- 134 82(trifluoromethyl)benzenesulfonamide4-chloro-N-[5-chloro-2-(isopropylthio)phenyl]-3- 379 72(trifluoromethyl)benzenesulfonamide4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)thio]phenyl}-3- 153 88(trifluoromethyl)benzenesulfonamide4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfinyl]phenyl}-3- 146 101(trifluoromethyl)benzenesulfonamide4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfonyl]phenyl}-3- 95 96(trifluoromethyl)benzenesulfonamide methyl 3-{[4-chloro-2-({[4-chloro-3-108 82 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}pro-panoate 4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-3- 19979 (trifluoromethyl)benzenesulfonamide4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-3- 94 85(trifluoromethyl)benzenesulfonamide4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfinyl]phenyl}- 92 833-(trifluoromethyl)benzenesulfonamide4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]phenyl}- 112 973-(trifluoromethyl)benzenesulfonamide ethyl {[4-chloro-2-({[4-chloro-3-141 79 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}acetate3-{[4-chloro-2-({[4-chloro-3- 1033 59(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-isopropylpropanamide 3-{[4-chloro-2-({[4-chloro-3- 506 80(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylpropanamide 3-{[4-chloro-2-({[4-chloro-3- 1788 93(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-isopropylpropanamide 3-{[4-chloro-2-({[4-chloro-3- 96 89(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylpropanamide 3-{[4-chloro-2-({[4-chloro-3- 797 99(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propan- amideN-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide NA 483,4-dichloro-N-[5-chloro-2- 44 87(methylsulfinyl)phenyl]benzenesulfonamideN-[5-chloro-2-(methylthio)phenyl]thiophene-2-sulfonamide NA 0N-[5-chloro-2-(methylsulfinyl)phenyl]thiophene-2- 1113 53 sulfonamide4-chloro-N-{5-chloro-2-[(3-nitrophenyl)sulfinyl]phenyl}-3- 509 85(trifluoromethyl)benzenesulfonamide 4-chloro-N-{5-chloro-2-[(3- 107 101hydroxycyclopentyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide 4-chloro-N-{5-chloro-2-[(3- 76 97hydroxycyclopentyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide4-chloro-N-[5-chloro-2-(ethylthio)phenyl]-3- 193 81(trifluoromethyl)benzenesulfonamide4-chloro-N-[5-chloro-2-(ethylsulfinyl)phenyl]-3- 50 78(trifluoromethyl)benzenesulfonamide4-chloro-N-[5-chloro-2-(ethylsulfonyl)phenyl]-3- 88 90(trifluoromethyl)benzenesulfonamideN-[5-chloro-2-(methylthio)phenyl]-1-benzofuran-2- 26 99 sulfonamideN-[5-chloro-2-(methylsulfinyl)phenyl]-1-benzofuran-2- 11 98 sulfonamideN-[5-chloro-2-(methylsulfonyl)phenyl]-1-benzofuran-2- 42 93 sulfonamideN-[5-chloro-2-(methylthio)phenyl]-4-methyl-3- 680 92nitrobenzenesulfonamide 4-chloro-N-[5-chloro-2- 406 94(methylthio)phenyl]benzenesulfonamide4-chloro-N-[5-chloro-2-(methylthio)phenyl]-3- 453 93methylbenzenesulfonamideN-[5-chloro-2-(methylsulfinyl)phenyl]-4-methyl-3- 181 101nitrobenzenesulfonamideN-[5-chloro-2-(methylsulfonyl)phenyl]-4-methyl-3- 207 89nitrobenzenesulfonamide 4-chloro-N-[5-chloro-2- 62 91(methylsulfinyl)phenyl]benzenesulfonamide 4-chloro-N-[5-chloro-2- 155 98(methylsulfonyl)phenyl]benzenesulfonamide4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3- 44 88methylbenzenesulfonamide 2-{[4-chloro-2-({[4-chloro-3- 118 92(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylacetamide 2-{[4-chloro-2-({[4-chloro-3- 268 100(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylacetamide 2-{[4-chloro-2-({[4-chloro-3- 462 98(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylacetamide 2-{[4-chloro-2-({[4-chloro-3- 329 91(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-methylacetamide 2-{[4-chloro-2-({[4-chloro-3- 469 96(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N-methylacetamide N-{2-[(2-aminoethyl)thio]-5-chlorophenyl}-4-chloro-3-1067 97 (trifluoromethyl)benzenesulfonamideN-[5-chloro-2-(methylthio)phenyl]-3-nitro-4- 491 90(trifluoromethyl)benzenesulfonamideN-[5-chloro-2-(methylsulfonyl)phenyl]-3-nitro-4- 213 97(trifluoromethyl)benzenesulfonamideN-[5-chloro-2-(methylthio)phenyl]-2,4- NA 87 difluorobenzenesulfonamideN-[5-chloro-2-(methylsulfonyl)phenyl]-2,4- 354 91difluorobenzenesulfonamide N-[5-chloro-2-(methylsulfinyl)phenyl]-2,4-236 98 difluorobenzenesulfonamideN-[5-chloro-2-(methylsulfinyl)phenyl]-3-nitro-4- 54 97(trifluoromethyl)benzenesulfonamideN-[5-chloro-2-(methylthio)phenyl]-5-methylfuran-2- 70 77 sulfonamideN-[5-chloro-2-(methylsulfinyl)phenyl]-5-methylfuran-2- 194 76sulfonamide N-[5-chloro-2-(methylsulfonyl)phenyl]-5-methylfuran-2- 99090 sulfonamide N-[5-chloro-2-(methylthio)phenyl]furan-2-sulfonamide 94093 N-[5-chloro-2-(methylsulfinyl)phenyl]furan-2-sulfonamide 2318 96N-[5-chloro-2-(methylsulfonyl)phenyl]furan-2-sulfonamide 345 994-chloro-N-[5-chloro-2-(methylthio)phenyl]-2- 25 95fluorobenzenesulfonamide 3-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-1924 94 fluorobenzenesulfonamide3-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-2- 116 101fluorobenzenesulfonamide3-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-2- 61 101fluorobenzenesulfonamide4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-2- 171 98fluorobenzenesulfonamide4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-2- 85 103fluorobenzenesulfonamideN-{2-[(2-aminoethyl)sulfinyl]-5-chlorophenyl}-4-chloro-3- 3531 84(trifluoromethyl)benzenesulfonamide4-chloro-N-{5-chloro-2-[(1H-imidazol-2- 190 84 ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide4-chloro-N-{5-chloro-2-[(1H-imidazol-2- 163 109ylmethyl)sulfinyl]phenyl}-3- (trifluoromethyl)benzenesulfonamide4-chloro-N-{5-chloro-2-[(1H-imidazol-2- 249 113ylmethyl)sulfonyl]phenyl}-3- (trifluoromethyl)benzenesulfonamide4-chloro-N-{5-chloro-2-[(1H-imidazol-4- 68 83 ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide4-chloro-N-{5-chloro-2-[(1H-imidazol-4- 158 111ylmethyl)sulfinyl]phenyl}-3- (trifluoromethyl)benzenesulfonamide4-chloro-N-{5-chloro-2-[(1H-imidazol-4- 51 108ylmethyl)sulfonyl]phenyl}-3- (trifluoromethyl)benzenesulfonamideN-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-1- 60 93benzofuran-2-sulfonamideN-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfinyl]phenyl}-1- 1898 108benzofuran-2-sulfonamideN-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfonyl]phenyl}-1- 1350 109benzofuran-2-sulfonamideN-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-1- 10 100benzofuran-2-sulfonamideN-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfinyl]phenyl}-1- 296 108benzofuran-2-sulfonamideN-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfonyl]phenyl}-1- 81 106benzofuran-2-sulfonamide 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 146100 chlorophenyl}thio)-N,N-dimethylpropanamide3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 160 104chlorophenyl}sulfinyl)-N,N-dimethylpropanamide3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 76 99chlorophenyl}sulfonyl)-N,N-dimethylpropanamideN-[2-({2-[(aminocarbonyl)amino]ethyl}thio)-5- 80 103chlorophenyl]-1-benzofuran-2-sulfonamideN-[2-({2-[(aminocarbonyl)amino]ethyl}sulfinyl)-5- 1891 64chlorophenyl]-1-benzofuran-2-sulfonamideN-[2-({2-[(aminocarbonyl)amino]ethyl}sulfonyl)-5- 1995 68chlorophenyl]-1-benzofuran-2-sulfonamide tert-butyl{6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 527 82chlorophenyl}sulfinyl)methyl]pyridin-2-yl}carbamateN-(2-{[(6-aminopyridin-2-yl)methyl]thio}-5-chlorophenyl)-1- 32 94benzofuran-2-sulfonamide N-(2-{[(6-aminopyridin-2-yl)methyl]sulfinyl}-5-28 99 chlorophenyl)-1-benzofuran-2-sulfonamideN-(2-{[(6-aminopyridin-2-yl)methyl]sulfonyl}-5- 15 102chlorophenyl)-1-benzofuran-2-sulfonamideN-(2-{[(6-amino-1-oxidopyridin-2-yl)methyl]sulfonyl}-5- 264 95chlorophenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[3-(dimethylamino)propyl]thio}phenyl)-1- 2043 106benzofuran-2-sulfonamideN-(5-chloro-2-{[3-(dimethylamino)propyl]sulfinyl}phenyl)-1- NA 81benzofuran-2-sulfonamideN-(5-chloro-2-{[3-(dimethylamino)propyl]sulfonyl}phenyl)-1- NA 96benzofuran-2-sulfonamideN-(5-chloro-2-{[3-(dimethylnitroryl)propyl]sulfonyl}phenyl)- NA 831-benzofuran-2-sulfonamide N-(2-{[4-chloro-2-({[4-chloro-3- 5190 98(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}eth- yl)acetamideN-(2-{[4-chloro-2-({[4-chloro-3- NA 97(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}ethyl) acetamideN-(5-chloro-2-{[(2-oxo-1,3-oxazolidin-5- 2128 79yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[(2-oxo-1,3-oxazolidin-5- 2561 98yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4- 2368 98yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4- NA 62yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4- NA 70yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamideN-{2-[(3-aminopropyl)thio]-5-chlorophenyl}-1-benzofuran- NA 1022-sulfonamide N-{2-[(3-aminopropyl)sulfinyl]-5-chlorophenyl}-1- NA 63benzofuran-2-sulfonamideN-{2-[(3-aminopropyl)sulfonyl]-5-chlorophenyl}-1- NA 82benzofuran-2-sulfonamide 4-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- NA54 chlorophenyl}sulfinyl)-N,N-dimethylbutanamide4-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 1003 98chlorophenyl}sulfonyl)-N,N-dimethylbutanamide5-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-1- 655 92benzofuran-2-sulfonamide5-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-1- 2047 74benzofuran-2-sulfonamideN-{5-chloro-2-[(1H-pyrazol-3-ylmethyl)thio]phenyl}-1- 16 99benzofuran-2-sulfonamideN-{5-chloro-2-[(1H-pyrazol-3-ylmethyl)sulfinyl]phenyl}-1- 634 99benzofuran-2-sulfonamideN-{5-chloro-2-[(1H-pyrazol-3-ylmethyl)sulfonyl]phenyl}-1- 367 102benzofuran-2-sulfonamideN-(5-chloro-2-{[(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5- 3077 21yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5- NA 0yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamideN-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 848 102chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}acetamideN-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 2685 79chlorophenyl}sulfinyl)methyl]-1,3-thiazol-2-yl}acetamideN-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- NA 87chlorophenyl}sulfonyl)methyl]-1,3-thiazol-2-yl}acetamideN-[5-chloro-2-(methylsulfinyl)phenyl]-4- 934 68isopropylbenzenesulfonamide 4-bromo-N-[5-chloro-2- 1329 76(methylthio)phenyl]benzenesulfonamideN-[5-chloro-2-(methylthio)phenyl]-4- 2032 71 iodobenzenesulfonamideN-[5-chloro-2-(methylsulfonyl)phenyl]-4- NA 0isopropylbenzenesulfonamide 4-bromo-N-[5-chloro-2- 116 94(methylsulfinyl)phenyl]benzenesulfonamideN-[5-chloro-2-(methylsulfinyl)phenyl]-4- 258 95 iodobenzenesulfonamide4-bromo-N-[5-chloro-2- 403 84 (methylsulfonyl)phenyl]benzenesulfonamideN-[5-chloro-2-(methylsulfonyl)phenyl]-4- 1068 92 iodobenzenesulfonamidetert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 2425 28chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}carbamateN-(2-{[(2-amino-1,3-thiazol-4-yl)methyl]thio}-5- 42 102chlorophenyl)-1-benzofuran-2-sulfonamide tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 2402 101chlorophenyl}sulfinyl)methyl]-1,3-thiazol-2-yl}carbamateN-(2-{[(2-amino-1,3-thiazol-4-yl)methyl]sulfinyl}-5- 262 100chlorophenyl)-1-benzofuran-2-sulfonamide tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- NA 72chlorophenyl}sulfonyl)methyl]-1,3-thiazol-2-yl}carbamateN-(2-{[(2-amino-1,3-thiazol-4-yl)methyl]sulfonyl}-5- 83 102chlorophenyl)-1-benzofuran-2-sulfonamideN-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-1- 35 91benzofuran-2-sulfonamideN-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-1- 22 97benzofuran-2-sulfonamideN-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]phenyl}-1- 76 100benzofuran-2-sulfonamideN-(5-chloro-2-{[(1-oxidopyridin-3-yl)methyl]sulfinyl}phenyl)- 646 1011-benzofuran-2-sulfonamideN-{5-chloro-2-[(pyridin-3-ylmethyl)sulfonyl]phenyl}-1- 32 93benzofuran-2-sulfonamide N-(5-chloro-2-{[(1-oxidopyridin-3- 1753 81yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamideN-{5-chloro-2-[(3-nitrobenzyl)thio]phenyl}-1-benzofuran-2- NA 63sulfonamide N-{5-chloro-2-[(3-methoxybenzyl)thio]phenyl}-1- 651 85benzofuran-2-sulfonamide N-(5-chloro-2-{[(5-nitro-1H-pyrazol-3- NA 91yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[(5-nitro-1H-pyrazol-3- 752 94yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamideN-(2-{[(5-amino-1H-pyrazol-3-yl)methyl]thio}-5- 25 105chlorophenyl)-1-benzofuran-2-sulfonamideN-(2-{[(5-amino-1H-pyrazol-3-yl)methyl]sulfinyl}-5- 1381 99chlorophenyl)-1-benzofuran-2-sulfonamideN-(2-{[(5-amino-1H-pyrazol-3-yl)methyl]sulfonyl}-5- 1867 98chlorophenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[(1-propyl-1H-imidazol-4- 1283 79yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[(1-propyl-1H-imidazol-4- 806 93yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[(1-propyl-1H-imidazol-4- 804 98yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamideN-{5-chloro-2-[(pyridin-2-ylmethyl)sulfinyl]phenyl}-1- 29 100benzofuran-2-sulfonamideN-{5-chloro-2-[(pyridin-2-ylmethyl)sulfonyl]phenyl}-1- 29 100benzofuran-2-sulfonamide N-(5-chloro-2-{[(1-oxidopyridin-2- 663 102yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[(1-oxidopyridin-2-yl)methyl]sulfinyl}phenyl)- 846 1011-benzofuran-2-sulfonamide tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 1999 40chlorophenyl}thio)methyl]pyridin-2-yl}carbamateN-(2-{[(2-aminopyridin-4-yl)methyl]thio}-5-chlorophenyl)-1- 80 100benzofuran-2-sulfonamide tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 2260 76chlorophenyl}sulfonyl)methyl]pyridin-2-yl}carbamate tert-butyl{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 2872 29chlorophenyl}sulfonyl)methyl]-1-oxidopyridin-2- yl}carbamateN-(2-{[(2-aminopyridin-4-yl)methyl]sulfinyl}-5- 865 101chlorophenyl)-1-benzofuran-2-sulfonamideN-(2-{[(2-aminopyridin-4-yl)methyl]sulfonyl}-5- 364 101chlorophenyl)-1-benzofuran-2-sulfonamideN-(2-{[(2-amino-1-oxidopyridin-4-yl)methyl]sulfonyl}-5- 9959 54chlorophenyl)-1-benzofuran-2-sulfonamideN-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-1-benzofuran- 42 922-sulfonamide N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-1- 39 96benzofuran-2-sulfonamideN-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-1- 23 90benzofuran-2-sulfonamide N-{5-chloro-2-[(3-hydroxybenzyl)thio]phenyl}-1-77 98 benzofuran-2-sulfonamideN-{5-chloro-2-[(3-hydroxybenzyl)sulfinyl]phenyl}-1- 112 103benzofuran-2-sulfonamideN-{5-chloro-2-[(3-hydroxybenzyl)sulfonyl]phenyl}-1- 56 96benzofuran-2-sulfonamide 3-{[4-chloro-2-({[4-chloro-3- 217 93(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylpropanamide 3-[(4-chloro-2-{[(2,4- 2154 43difluorophenyl)sulfonyl]amino}phenyl)thio]-N,N- dimethylpropanamideN-(2-{[(5-amino-4H-1,2,4-triazol-3-yl)methyl]thio}-5- 32 103chlorophenyl)-1-benzofuran-2-sulfonamideN-(2-{[(5-amino-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}-5- NA 48chlorophenyl)-1-benzofuran-2-sulfonamide 3-[(4-chloro-2-{[(2,4- 1477 93difluorophenyl)sulfonyl]amino}phenyl)sulfinyl]-N,N- dimethylpropanamide3-[(4-chloro-2-{[(2,4- 1577 89difluorophenyl)sulfonyl]amino}phenyl)sulfonyl]-N,N- dimethylpropanamide3-[(4-chloro-2-{[(4-chloro-2- 771 78fluorophenyl)sulfonyl]amino}phenyl)thio]-N,N- dimethylpropanamide3-[(4-chloro-2-{[(4-chloro-2- 221 99fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]-N,N- dimethylpropanamide3-[(4-chloro-2-{[(4-chloro-2- 211 97fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]-N,N- dimethylpropanamideN-{5-chloro-2-[(2-pyridin-2-ylethyl)thio]phenyl}-1- 713 84benzofuran-2-sulfonamideN-(5-chloro-2-{[2-(1H-pyrazol-4-yl)ethyl]sulfinyl}phenyl)-1- 1061 67benzofuran-2-sulfonamideN-{5-chloro-2-[(2-pyridin-2-ylethyl)sulfinyl]phenyl}-1- 153 86benzofuran-2-sulfonamideN-{5-chloro-2-[(2-pyridin-2-ylethyl)sulfonyl]phenyl}-1- 197 93benzofuran-2-sulfonamideN-(5-chloro-2-{[2-(1H-pyrazol-4-yl)ethyl]thio}phenyl)-1- 412 91benzofuran-2-sulfonamideN-(5-chloro-2-{[2-(1H-pyrazol-4-yl)ethyl]sulfonyl}phenyl)-1- 570 93benzofuran-2-sulfonamide N-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-279 89 yl)ethyl]thio}phenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4- 3047 83yl)ethyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4- 1088 96yl)ethyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamideN-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]thio}phenyl)-1- 94 76benzofuran-2-sulfonamideN-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]sulfinyl}phenyl)- 79 951-benzofuran-2-sulfonamide N-(5-chloro-2-{[(2-fluoropyridin-3- 79 88yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamideN-{5-chloro-2-[(trifluoromethyl)thio]phenyl}-1-benzofuran-2- 333 92sulfonamide N-{5-chloro-2-[(trifluoromethyl)sulfonyl]phenyl}-1- 73 91benzofuran-2-sulfonamideN-{5-chloro-2-[(trifluoromethyl)sulfinyl]phenyl}-1- 19 89benzofuran-2-sulfonamideN-[2-(benzylthio)-5-chlorophenyl]-1-benzofuran-2- 129 90 sulfonamideN-[2-(benzylsulfinyl)-5-chlorophenyl]-1-benzofuran-2- 27 85 sulfonamideN-[2-(benzylsulfonyl)-5-chlorophenyl]-1-benzofuran-2- 34 90 sulfonamideN-{2-[(3-aminobenzyl)thio]-5-fluorophenyl}-1-benzofuran-2- 55 97sulfonamide N-{5-fluoro-2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-314 96 2-sulfonamide N-{2-[(3-aminobenzyl)sulfinyl]-5-fluorophenyl}-1-38 91 benzofuran-2-sulfonamideN-{5-fluoro-2-[(3-nitrobenzyl)sulfonyl]phenyl}-1- 693 81benzofuran-2-sulfonamideN-{2-[(3-aminobenzyl)sulfonyl]-5-fluorophenyl}-1- 22 90benzofuran-2-sulfonamide N-{2-[(3-aminobenzyl)thio]-5-methoxyphenyl}-1-1397 100 benzofuran-2-sulfonamideN-{2-[(3-aminobenzyl)sulfonyl]-5-methoxyphenyl}-1- 176 107benzofuran-2-sulfonamideN-{2-[(3-aminobenzyl)thio]phenyl}-1-benzofuran-2- 676 105 sulfonamideN-{2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2- 653 97 sulfonamideN-{2-[(3-aminobenzyl)sulfinyl]phenyl}-1-benzofuran-2- 58 110 sulfonamideN-{5-methoxy-2-[(3-nitrobenzyl)sulfinyl]phenyl}-1- 845 84benzofuran-2-sulfonamideN-{2-[(3-aminobenzyl)sulfinyl]-5-methoxyphenyl}-1- 85 100benzofuran-2-sulfonamideN-{2-[(3-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2- 2131 83sulfonamide N-{2-[(3-aminobenzyl)sulfonyl]phenyl}-1-benzofuran-2- 41 94sulfonamide N-{5-chloro-2-[(4-nitrobenzyl)thio]phenyl}-1-benzofuran-2-147 82 sulfonamideN-{2-[(2-aminobenzyl)thio]-5-chlorophenyl}-1-benzofuran- 100 912-sulfonamide N-{5-chloro-2-[(4-nitrobenzyl)sulfonyl]phenyl}-1- 2159 20benzofuran-2-sulfonamideN-{2-[(4-aminobenzyl)sulfonyl]-5-chlorophenyl}-1- 90 104benzofuran-2-sulfonamideN-{5-chloro-2-[(2-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran- 75 952-sulfonamide N-{2-[(2-aminobenzyl)sulfinyl]-5-chlorophenyl}-1- 115 93benzofuran-2-sulfonamideN-{2-[(2-aminobenzyl)sulfonyl]-5-chlorophenyl}-1- 129 98benzofuran-2-sulfonamide N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-2,4-3244 64 difluorobenzenesulfonamideN-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-4-chloro-2- 2824 88fluorobenzenesulfonamideN-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-2,4- 718 89difluorobenzenesulfonamideN-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-2,4- 443 99difluorobenzenesulfonamideN-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-4-chloro-2- 248 96fluorobenzenesulfonamideN-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-4-chloro-2- 113 95fluorobenzenesulfonamideN-{5-chloro-2-[(pyrimidin-2-ylmethyl)thio]phenyl}-1- 549 100benzofuran-2-sulfonamideN-{5-chloro-2-[(pyrimidin-2-ylmethyl)sulfinyl]phenyl}-1- 506 104benzofuran-2-sulfonamideN-{5-chloro-2-[(pyrimidin-2-ylmethyl)sulfonyl]phenyl}-1- 151 104benzofuran-2-sulfonamide N-{2-[(3-aminobenzyl)thio]-5- 3102 40chlorophenyl}benzenesulfonamideN-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-4- 3894 95chlorobenzenesulfonamide N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-3-1458 95 chlorobenzenesulfonamide N-{2-[(3-aminobenzyl)sulfonyl]-5- 123952 chlorophenyl}benzenesulfonamide N-{2-[(3-aminobenzyl)sulfinyl]-5-2564 62 chlorophenyl}benzenesulfonamideN-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-4- 421 99chlorobenzenesulfonamideN-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-4- 159 99chlorobenzenesulfonamideN-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-3- 246 91chlorobenzenesulfonamideN-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-3- 159 93chlorobenzenesulfonamideN-[2-(benzylthio)-5-cyanophenyl]-1-benzofuran-2- 3837 78 sulfonamideN-[2-(benzylsulfinyl)-5-cyanophenyl]-1-benzofuran-2- 50 105 sulfonamideN-[2-(benzylsulfonyl)-5-cyanophenyl]-1-benzofuran-2- 56 95 sulfonamide

What is claimed is:
 1. A compound having Formula I, its enantiomers,diastereoisomers, hydrates, solvates, crystal forms and individualisomers, tautomers or a pharmaceutically acceptable salt thereof:

wherein: R¹ is H; R² is substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₃₋₈ cycloalkyl or is substituted orunsubstituted C₃₋₈ cycloalkenyl; R⁵ is —S—, —S(O)—, or —S(O)₂—; R⁶ is4-chloro-3-trifluoromethyl-phenyl; R¹⁷ is H, substituted orunsubstituted C₁₋₆ alkyl, halogen, substituted or unsubstituted —OC₁₋₆alkyl, CN, C(O)R¹⁹, NR²⁰R²¹ or hydroxyl; R¹⁸ is H, substituted orunsubstituted C₁₋₆ alkyl, halogen, substituted or unsubstituted —OC₁₋₆alkyl, CN, C(O)R²², NR²³R²⁴ or hydroxyl; R⁷ is halogen, CN, substitutedor unsubstituted —OC₁₋₆ alkyl, substituted or unsubstituted C₁₋₆ alkylor is substituted or unsubstituted C₃₋₈ cycloalkyl; R⁸ is H, substitutedor unsubstituted C₁₋₆ alkyl, halogen, substituted or unsubstituted—OC₁₋₆ alkyl, or hydroxyl; R¹⁹ is H, OH or substituted or unsubstitutedC₁₋₆ alkyl; R²⁰ is H or substituted or unsubstituted C₁₋₆ alkyl; R²¹ isH or substituted or unsubstituted C₁₋₆ alkyl; R²² is H, OH orsubstituted or unsubstituted C₁₋₆ alkyl; R²³ is H or substituted orunsubstituted C₁₋₆ alkyl; R²⁴ is H or substituted or unsubstituted C₁₋₆alkyl.
 2. A compound according to claim 1, wherein: R⁵ is S.
 3. Acompound according to claim 1, wherein: R⁵ is —S(O)—.
 4. A compoundaccording to claim 1, wherein: R⁵ is —S(O)₂—.
 5. A compound according toclaim 1, wherein: R² is methyl, isopropyl, 2-hydroxyethyl,methylpropionate, 2-methylpyridine, 3-methylpyridine, ethylacetate,N,N-dimethylpropanamide, N-isopropylpropanamide,N-(propan-2-yl)propanamide, propanamide hydroxycyclopent-3-yl, ethyl,N,N-dimethylacetamide, N-methylacetamide, 2-aminoethyl,H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl or ethyl-acetamide.
 6. Acompound according to claim 1, wherein: R¹⁷ is H, substituted orunsubstituted C₁₋₆ alkyl or halogen; R¹⁸ is H, substituted orunsubstituted C₁₋₆ alkyl or halogen; R⁷ is halogen, CN, —OC₁₋₆ alkyl,substituted or unsubstituted C₁₋₆ alkyl or substituted or unsubstitutedC₃₋₈ cycloalkyl; and R⁸ is H, substituted or unsubstituted C₁₋₆ alkyl orhalogen.
 7. A compound according to claim 1, wherein: R¹⁷ is H; R¹⁸ isH; R⁷ is halogen, CN or —OC₁₋₆ alkyl; and R⁸ is H.
 8. A compoundaccording to claim 1, wherein: R² is methyl, isopropyl, 2-hydroxyethyl,methylpropionate, 2-methylpyridine, 3-methylpyridine, ethylacetate,N,N-dimethylpropanamide, N-isopropylpropanamide,N-(propan-2-yl)propanamide, propanamide hydroxycyclopent-3-yl, ethyl,N,N-dimethylacetamide, N-methylacetamide, 2-aminoethyl,H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl or ethyl-acetamide; R⁵ is—S—, —S(O)—, or —S(O)₂—; R¹⁷ is H; R¹⁸ is H; R⁷ is halogen, CN or —OC₁₋₆alkyl; and R⁸ is H.
 9. A compound according to claim 8, wherein: R⁵ is—S(O).
 10. A compound according to claim 8, wherein: R⁵ is —S(O)₂—. 11.A compound according to claim 8, wherein: R⁵ is S.
 12. A compoundaccording to claim 1, selected from:4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-[5-chloro-2-(methylsulfanyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-[5-chloro-2-(propan-2-ylsulfanyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfanyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;methyl3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propanoate;4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfanyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfanyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;ethyl{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}acetate;3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}-N-(propan-2-yl)propanamide;3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}-N,N-dimethylpropanamide;3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-(propan-2-yl)propanamide;3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylpropanamide;3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propanamide;4-chloro-N-{5-chloro-2-[(3-nitrophenyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(3-hydroxycyclopentyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(3-hydroxycyclopentyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-[5-chloro-2-(ethylsulfanyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-[5-chloro-2-(ethylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-[5-chloro-2-(ethylsulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}-N,N-dimethylacetamide;2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylacetamide;2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylacetamide;2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-methylacetamide;2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N-methylacetamide;N-{2-[(2-aminoethyl)sulfanyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide;3-chloro-N-[5-chloro-2-(methylsulfanyl)phenyl]-2-fluorobenzenesulfonamide;N-{2-[(2-aminoethyl)sulfinyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfanyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfanyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;N-(2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}ethyl)acetamide;N-(2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}ethyl)acetamide;and3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylpropanamide.13. A pharmaceutical composition comprising as active ingredient atherapeutically effective amount of a compound according to claim 1, anda pharmaceutically acceptable adjuvant, diluents or carrier.
 14. Apharmaceutical composition according to claim 1, wherein the compound isselected from:4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-[5-chloro-2-(methylsulfanyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-[5-chloro-2-(propan-2-ylsulfanyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfanyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;methyl3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propanoate;4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfanyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfanyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;ethyl{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}acetate;3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}-N-(propan-2-yl)propanamide;3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}-N,N-dimethylpropanamide;3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-(propan-2-yl)propanamide;3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylpropanamide;3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propanamide;4-chloro-N-{5-chloro-2-[(3-nitrophenyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(3-hydroxycyclopentyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(3-hydroxycyclopentyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-[5-chloro-2-(ethylsulfanyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-[5-chloro-2-(ethylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-[5-chloro-2-(ethylsulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide;2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}-N,N-dimethylacetamide;2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylacetamide;2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylacetamide;2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-methylacetamide;2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N-methylacetamide;N-{2-[(2-aminoethyl)sulfanyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide;3-chloro-N-[5-chloro-2-(methylsulfanyl)phenyl]-2-fluorobenzenesulfonamide;N-{2-[(2-aminoethyl)sulfinyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfanyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfanyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide;N-(2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}ethyl)acetamide;N-(2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}ethyl)acetamide;and3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylpropanamide.